Imidazopyridazine compounds

ABSTRACT

The present invention is directed to compounds of Formula I: 
                         
or a pharmaceutically acceptable salt thereof, wherein the substituents R 1 , R 3 , R 6 , R 7 , and b are as defined herein. The invention is also directed to pharmaceutical compositions comprising the compounds, methods of treatment using the compounds, and methods of preparing the compounds.

This application is a continuation application of U.S. patentapplication Ser. No. 14/817,606, filed Aug. 4, 2015, which claims thebenefit under 35 U.S.C. 119(e) of U.S. Provisional Patent ApplicationNo. 62/033,684, filed on Aug. 6, 2014, and U.S. Provisional PatentApplication No. 62/157,129, filed May 5, 2015, the disclosures of whichare hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to imidazopyridazine compounds of FormulaI, which are inhibitors of PDE4 isozymes, especially with a bindingaffinity for the PDE4B isoform, and to the use of such compounds inmethods for treating central nervous system (CNS), metabolic, autoimmuneand inflammatory diseases or disorders.

BACKGROUND OF THE INVENTION

Phosphodiesterases (PDEs) are a class of intracellular enzymes thatcleave the phosphodiester bond in second messenger molecules adenosine3′,5′-cyclic monophosphate (cGMP) and guanosine 3′,5′-cyclicmonophosphate (cGMP). The cyclic nucleotides cAMP and cGMP serve assecondary messengers in various cellular pathways.

cAMP functions as a second messenger regulating many intracellularprocesses within the body. One example is in the neurons of the centralnervous system, where the activation of cAMP-dependent kinases and thesubsequent phosphorylation of proteins are involved in acute regulationof synaptic transmission as well as neuronal differentiation andsurvival. The complexity of cyclic nucleotide signaling is indicated bythe molecular diversity of the enzymes involved in the synthesis anddegradation of cAMP. There are at least ten families of adenylylcyclases, and eleven families of phosphodiesterases. Furthermore,different types of neurons are known to express multiple isozymes ofeach of these classes, and there is good evidence forcompartmentalization and specificity of function for different isozymeswithin a given neuron.

A principal mechanism for regulating cyclic nucleotide signaling is viaphosphodiesterase-catalyzed cyclic nucleotide catabolism. The elevenknown families of PDEs are encoded by 21 different genes; each genetypically yields multiple splice variants that further contribute to theisozyme diversity. The PDE families are distinguished functionally basedon cyclic nucleotide substrate specificity, mechanism(s) of regulation,and sensitivity to inhibitors. Furthermore, PDEs are differentiallyexpressed throughout the organism, including in the central nervoussystem. As a result of these distinct enzymatic activities andlocalization, different PDEs' isozymes can serve distinct physiologicalfunctions. Furthermore, compounds that can selectively inhibit distinctPDE isozymes may offer particular therapeutic effects, fewer sideeffects, or both (Deninno, M., Future Directions in PhosphodiesteraseDrug Discovery. Bioorganic and Medicinal Chemistry Letters 2012, 22,6794-6800).

The present invention relates to compounds having a binding affinity forthe fourth family of PDEs (i.e., PDE4A, PDE4B, PDE4C, and PDE4D), and,in particular, a binding affinity for the PDE4B isoform.

The PDE4 isozymes carry out selective, high-affinity hydrolyticdegradation of the second messenger adenosine 3′,5′-cyclic monophosphate(cAMP). Beneficial pharmacological effects resulting from thatinhibition have been shown in a variety of disease models. A number ofPDE4 inhibitors have been discovered in recent years. For example,Roflumilast (Daliresp®), marketed by Forest Pharmaceuticals, Inc., isapproved for severe chronic obstructive pulmonary disease (COPD) todecrease the number of flare-ups or prevent exacerbations of COPDsymptoms. Apremilast (Otezla®) has been approved by the U.S. Food andDrug Administration for the treatment of adults with active psoriaticarthritis.

While beneficial pharmacological activity of PDE4 inhibitors has beenshown, a common side effect of these treatments has been the inductionof gastrointestinal symptoms such as nausea, emesis, and diarrhea, whichare currently believed to be associated with inhibition of the PDE4Disoform. Attempts have been made to develop compounds with an affinityfor the PDE4B isoform over the PDE4D isoform (See: Donnell, A. F. etal., Identification of pyridazino[4,5-b]indolizines as selective PDE4Binhibitors. Bioorganic & Medicinal Chemistry Letters 2010, 20, 2163-7;and Naganuma, K. et al., Discovery of selective PDE4B inhibitors.Bioorganic and Medicinal Chemistry Letters 2009, 19, 3174-6). However,there remains a need to develop selective PDE4 inhibitors, especiallythose having an affinity for the PDE4B isoform. In particular, compoundswith enhanced binding affinity for the PDE4B isoform over the PDE4Disoform are anticipated to be useful in the treatment of variousdiseases and disorders of the central nervous system (CNS). Thediscovery of selected compounds of the present invention addresses thiscontinued need, and provides additional therapies for the treatment ofvarious diseases and disorders of the central nervous system (CNS), aswell as metabolic, autoimmune and inflammatory diseases or disorders.

Treatment with the PDE4B inhibitors of the present invention may alsolead to a decrease in gastrointestinal side effects (e.g., nausea,emesis and diarrhea) believed to be associated with inhibition of thePDE4D isoform (Robichaud, A. et al., Deletion of Phosphodiesterase 4D inMice Shortens α2-Adrenoreceptor-Mediated Anesthesia, A BehavioralCorrelate of Emesis. Journal of Clinical Investigation 2002, 110,1045-1052).

SUMMARY OF THE INVENTION

The present invention is directed to compounds of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of—(CH₂)_(m)—(C₃-C₈)cycloalkyl, —(CH₂)_(m)-(4- to10-membered)heterocycloalkyl, —(CH₂)_(m)—(C₆-C₁₀)aryl and —(CH₂)_(m)-(5-to 14-membered)-heteroaryl, and, where chemically permissible, the(C₃-C₈)cycloalkyl, (4- to 10-membered)heterocycloalkyl, (C₆-C₁₀)aryl and(5- to 14-membered)heteroaryl moieties are optionally substituted withone to five R²;

when present, each R² is independently selected from the groupconsisting of halogen, oxo, cyano, hydroxy, —SF₅, nitro, optionallysubstituted (C₁-C₆)alkyl, optionally substituted (C₂-C₆)alkenyl,optionally substituted (C₂-C₆)alkynyl, optionally substituted(C₁-C₆)alkylthio, optionally substituted (C₁-C₆)alkoxy, —N(R⁴)(R⁵),—N(R⁴)(C═(O)R⁵), —C(═O)N(R⁴)(R⁵), —C(═O)—O—N(R⁴)(R⁵), —C(═O)—R⁴,—C(═O)—OR⁴, and optionally substituted (C₃-C₈)cycloalkyl;

when present, each R³ is independently selected from the groupconsisting of halogen, cyano, hydroxy, —SF₅, nitro, optionallysubstituted (C₁-C₆)alkyl, optionally substituted (C₂-C₆)alkenyl,optionally substituted (C₂-C₆)alkynyl, optionally substituted(C₁-C₆)alkylthio, optionally substituted (C₁-C₆)alkoxy, —N(R⁴)(R⁵),—N(R⁴)(C═(O)R⁵), —C(═O)N(R⁴)(R⁵), —C(═O)—O—N(R⁴)(R⁵), —C(═O)—R⁴, and—C(═O)—OR⁴;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen and optionally substituted (C₁-C₆)alkyl;

R⁶ and R⁷ are each independently selected from the group consisting ofhydrogen, optionally substituted (C₁-C₆)alkyl,—(CH₂)_(n)—(C₃-C₈)cycloalkyl, —(CH₂)_(n)-(4- to 10-membered)heterocycloalkyl, —(CH₂)_(n)—(C₆-C₁₀)aryl, and —(CH₂)_(n)-(5- to10-membered)heteroaryl, and where chemically permissible, the(C₃-C₈)cycloalkyl, (4- to 10-membered)heterocycloalkyl, (C₆-C₁₀)aryl,and (5- to 10-membered)heteroaryl are optionally substituted with one tofive R⁸; or

R⁶ and R⁷ taken together with the nitrogen to which they are attachedform a (4- to 10-membered)heterocycloalkyl, and where chemicallypermissible, the (4- to 10-membered)-heterocycloalkyl is optionallysubstituted with one to five R⁹;

when present, each R⁸ is independently selected from the groupconsisting of halogen, oxo, cyano, hydroxy, —SF₅, nitro, optionallysubstituted (C₁-C₆)alkyl, optionally substituted (C₂-C₆)alkenyl,optionally substituted (C₂-C₆)alkynyl, optionally substituted(C₁-C₆)alkylthio, optionally substituted (C₁-C₆)alkoxy, —N(R⁴)(R⁵),—N(R⁴)(C═(O)R⁵), —C(═O)N(R⁴)(R⁵), —C(═O)—O—N(R⁴)(R⁵), —C(═O)—R⁴, and—C(═O)—OR⁴;

when present, each R⁹ is independently selected from the groupconsisting of halogen, oxo, cyano, hydroxy, —SF₅, nitro, optionallysubstituted (C₁-C₆)alkyl, optionally substituted (C₂-C₆)alkenyl,optionally substituted (C₂-C₆)alkynyl, optionally substituted(C₁-C₆)alkylthio, optionally substituted (C₁-C₆)alkoxy, —N(R⁴)(R⁵),—N(R⁴)(C═(O)R⁵), —C(═O)N(R⁴)(R⁵), —C(═O)—O—N(R⁴)(R⁵), —C(═O)—R⁴, and—C(═O)—OR⁴;

b is represented by an integer selected from 0, 1, 2, or 3;

m is represented by an integer selected from 0, 1, or 2; and

n is represented by an integer selected from 0, 1, 2, 3 or 4.

Compounds of the invention include Examples 1-104 or a pharmaceuticallyacceptable salt thereof as described herein.

The compounds of Formula I are inhibitors of the PDE4B isoform.

The compounds of Formula I are useful for treating or preventingdiseases and/or disorders of the central nervous system (CNS), pain,trauma, cardiologic, thrombotic, metabolic, autoimmune and inflammatorydiseases or disorders, and disorders associated with enhancedendothelial activity/impaired endothelial barrier function.

The present invention is also directed to the use of the compoundsdescribed herein, or a pharmaceutically acceptable salt thereof, in thepreparation of a medicament for the treatment or prevention of acondition amenable to modulation of the PDE4B gene family (i.e., PDE4Benzymes).

The present invention is also directed to pharmaceutically acceptableformulations containing an admixture of a compound(s) of the presentinvention and at least one excipient formulated into a pharmaceuticaldosage form. Examples of such dosage forms include tablets, capsules,suppositories, gels, creams, ointments, lotions, solutions/suspensionsfor injection (e.g., depot), aerosols for inhalation andsolutions/suspensions for oral ingestion.

DETAILED DESCRIPTION OF THE INVENTION

The headings within this document are being utilized only to expediteits review by the reader. They should not be construed as limiting theinvention or claims in any manner.

Definitions and Exemplifications

As used throughout this application, including the claims, the followingterms have the meanings defined below, unless specifically indicatedotherwise. The plural and singular should be treated as interchangeable,other than the indication of number:

As used herein, the term “n-membered” where n is an integer typicallydescribes the number of ring-forming atoms in a moiety where the numberof ring-forming atoms is n. For example, pyridine is an example of a6-membered heteroaryl ring and thiazole is an example of a 5-memberedheteroaryl group.

At various places in the present specification, substituents ofcompounds of the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “(C₁-C₆)alkyl” is specifically intended to include C₁alkyl (methyl), C₂ alkyl (ethyl), C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆alkyl. For another example, the term “a (5- to10-membered)heterocycloalkyl group” is specifically intended to includeany 5-, 6-, 7-, 8-, 9-, and 10-membered heterocycloalkyl group.

The term “(C₁-C₆)alkyl”, as used herein, refers to a saturated,branched- or straight-chain alkyl group containing from 1 to 6 carbonatoms, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl,neopentyl, and n-hexyl.

The term “optionally substituted (C₁-C₆)alkyl”, as used herein, refersto a (C₁-C₆)alkyl as defined above, in which one or more hydrogen atomsare replaced by a substituent selected from the group consisting ofhalogen, oxo, cyano, hydroxy, —SF₅, nitro, —N(R⁴)(R⁵), —N(R⁴)(C(═O)R⁵),—N(R⁴)C(═O)—OR⁵, —C(═O)—N(R⁴)(R⁵), —C(═O)—O—N(R⁴)(R⁵), —C(═O)—R⁴,—C(═O)—OR⁴, and (C₃-C₈)cycloalkyl, in which R⁴ and R⁵ are eachindependently hydrogen or optionally substituted (C₁-C₆)alkyl. Forexample, a (C₁-C₆)alkyl moiety can be substituted with one or morehalogen atoms to form a “halo(C₁-C₆)alkyl”. Representative examples of ahalo(C₁-C₆)alkyl include, but are not limited to, fluoromethyl,difluoromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and2-chloro-3-fluoropentyl.

The term “(C₂-C₆)alkenyl” refers to an aliphatic hydrocarbon having from2 to 6 carbon atoms and having at least one carbon-carbon double bond,including straight chain or branched chain groups having at least onecarbon-carbon double bond. Representative examples include, but are notlimited to, ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. When thecompounds of the invention contain a (C₂-C₆)alkenyl group, the compoundmay exist as the pure E (entgegen) form, the pure Z (zusammen) form, orany mixture thereof.

The term “optionally substituted (C₂-C₆)alkenyl” refers to a(C₂-C₆)alkenyl as defined above, in which one or more hydrogen atoms arereplaced by a substituent selected from the group consisting of halogen,oxo, cyano, hydroxy, —SF₅, nitro, —N(R⁴)(R⁵), —N(R⁴)(C(═O)R⁵),—N(R⁴)C(═O)—OR⁵, —C(═O)—N(R⁴)(R⁵), —C(═O)—O—N(R⁴)(R⁵), —C(═O)—R⁴,—C(═O)—OR⁴, and (C₃-C₈)cycloalkyl, in which R⁴ and R⁵ are eachindependently hydrogen or optionally substituted (C₁-C₆)alkyl.

The term “(C₂-C₆)alkynyl” refers to an aliphatic hydrocarbon having twoto six carbon atoms and at least one carbon-carbon triple bond,including straight chains and branched chains having at least onecarbon-carbon triple bond. Representative examples include, but are notlimited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

The term “optionally substituted (C₂-C₆)alkynyl” refers to a(C₂-C₆)alkynyl as defined above, in which one or more hydrogen atoms arereplaced by a substituent selected from the group consisting of halogen,oxo, cyano, hydroxy, —SF₅, —N(R⁴)(R⁵), —N(R⁴)(C(═O)R⁵), —N(R⁴)C(═O)—OR⁵,—C(═O)—N(R⁴)(R⁵), —C(═O)—O—N(R⁴)(R⁵), —C(═O)—R⁴, —C(═O)—OR⁴, and(C₃-C₈)cycloalkyl, in which R⁴ and R⁵ are each independently hydrogen oroptionally substituted (C₁-C₆)alkyl.

The term “(C₁-C₆)alkoxy” as used herein, refers to a (C₁-C₆)alkyl group,as defined above, attached to the parent molecular moiety through anoxygen atom. Representative examples of a (C₁-C₆)alkoxy include, but arenot limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,tert-butoxy, pentyloxy, and hexyloxy.

The term “optionally substituted (C₁-C₆)alkoxy” as used herein, refersto a (C₁-C₆)alkoxy group, as defined above, in which one or morehydrogen atoms are replaced by a substituent selected from the groupconsisting of halogen, oxo, cyano, hydroxy, —SF₅, nitro, —N(R⁴)(R⁵),—N(R⁴)(C(═O)R⁵), —N(R⁴)C(═O)—OR⁵, —C(═O)—N(R⁴)(R⁵), —C(═O)—O—N(R⁴)(R⁵),—C(═O)—R⁴, —C(═O)—OR⁴, and (C₃-C₈)cycloalkyl, in which R⁴ and R⁵ areeach independently hydrogen or optionally substituted (C₁-C₆)alkyl. Forexample, a (C₁-C₆)alkoxy can be substituted with one or more halogenatoms to form a “halo(C₁-C₆)alkoxy”. Representative examples of ahalo(C₁-C₆)alkoxy include, but are not limited to, fluoromethoxy,difluoromethoxy, 2-fluoroethoxy, trifluoromethoxy, andpentafluoroethoxy.

The term “(C₁-C₆)alkythio”, as used herein, refers to a (C₁-C₆)alkylgroup, as defined above, attached to the parent molecular moiety througha sulfur atom. Representative examples of a (C₁-C₆)alkylthio include,but are not limited to, methylthio, ethylthio, propylthio, and the like.

The term “optionally substituted (C₁-C₆)alkythio”, as used herein,refers to a (C₁-C₆)alkylthio group, as defined above, in which one ormore hydrogen atoms are replaced by a substituent selected from thegroup consisting of halogen, oxo, cyano, hydroxy, —SF₅, nitro,—N(R⁴)(R⁵), —N(R⁴)(C(═O)R⁵), —N(R⁴)C(═O)—OR⁵, —C(═O)—N(R⁴)(R⁵),—C(═O)—O—N(R⁴)(R⁵), —C(═O)—R⁴, —C(═O)—OR⁴, and (C₃-C₈)cycloalkyl, inwhich R⁴ and R⁵ are each independently hydrogen or optionallysubstituted (C₁-C₆)alkyl.

As used herein, the term “(C₃-C₈)cycloalkyl” refers to a carbocyclicsubstituent obtained by removing hydrogen from a saturated carbocyclicmolecule wherein the cyclic framework has 3 to 8 carbons. A“(C₃-C₆)cycloalkyl” refers to a carbocyclic substituent obtained byremoving hydrogen from a saturated carbocyclic molecule having from 3 to6 carbon atoms. A “cycloalkyl” may be a monocyclic ring, examples ofwhich include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. Also included in the definition ofcycloalkyl are unsaturated non-aromatic cycloalkyls such as, but notlimited to, cyclohexenyl, cyclohexadienyl, cyclopentenyl, cycloheptenyl,and cyclooctenyl. Alternatively, a cycloalkyl may contain more than onering such as a “(C₄-C₈)bicycloalkyl”. The term “(C₄-C₈)bicycloalkyl”refers to a bicyclic ring system containing from 4 to 8 carbon atoms.The bicycloalkyl may be fused, such as bicyclo[1.1.0]butanyl,bicyclo[2.1.0]pentanyl, bicyclo[2.2.0]hexanyl, bicyclo[3.1.0]hexanyl,bicyclo[3.2.0]heptanyl, and bicyclo[3.3.0]-octanyl. The term“bicycloalkyl” also includes bridged bicycloalkyl systems such as, butnot limited to, bicyclo[2.2.1]heptanyl and bicyclo[1.1.1]pentanyl.

The term “optionally substituted “(C₃-C₈)cycloalkyl” refers to a(C₃-C₈)cycloalkyl, as defined above, in which one or more hydrogen atomsare replaced by a substituent selected from the group consisting ofhalogen, oxo, cyano, hydroxy, —SF₅, nitro, —N(R⁴)(R⁵), —N(R⁴)(C(═O)R⁵),—N(R⁴)C(═O)—OR⁵, —C(═O)—N(R⁴)(R⁵), —C(═O)—O—N(R⁴)(R⁵), —C(═O)—R⁴,—C(═O)—OR⁴, and (C₃-C₈)cycloalkyl, in which R⁴ and R⁵ are eachindependently hydrogen or optionally substituted (C₁-C₆)alkyl.

A “heterocycloalkyl,” as used herein, refers to a cycloalkyl as definedabove, wherein at least one of the ring carbon atoms is replaced with aheteroatom selected from nitrogen, oxygen or sulfur. The term “(4- to6-membered)heterocycloalkyl” means the heterocycloalkyl substituentcontains a total of 4 to 6 ring atoms, at least one of which is aheteroatom. The term “(4- to 8-membered)heterocycloalkyl” means theheterocycloalkyl substituent contains a total of 4 to 8 ring atoms, atleast one of which is a heteroatom. A “(4- to10-membered)heterocycloalkyl” means the heterocycloalkyl substituentcontains a total of 4 to 10 ring atoms. A “(6-membered)heterocycloalkyl”means the heterocycloalkyl substituent contains a total of 6 ring atoms,at least one of which is a heteroatom. A “(5-membered)heterocycloalkyl”means the heterocycloalkyl substituent contains a total of 5 ring atomsat least one of which is a heteroatom. A heterocycloalkyl may be asingle ring with up to 10 total members. Alternatively, aheterocycloalkyl as defined above may comprise 2 or 3 rings fusedtogether, wherein at least one such ring contains a heteroatom as a ringatom (i.e., nitrogen, oxygen, or sulfur). The heterocycloalkylsubstituent may be attached to the imidazopyridazine core of thecompounds of the present invention via a nitrogen atom having theappropriate valence, or via any ring carbon atom. The heterocycloalkylsubstituent may also be attached to the nitrogen of the amide moiety onthe imidazopyridazine core. The heterocycloalkyl moiety may beoptionally substituted with one or more substituents at a nitrogen atomhaving the appropriate valence, or at any available carbon atom.

Also included in the definition of “heterocycloalkyl” areheterocycloalkyls that are fused to a phenyl or naphthyl ring or to aheteroaryl ring such as, but not limited to, a pyridinyl ring or apyrimidinyl ring.

Examples of heterocycloalkyl rings include, but are not limited to,azetidinyl, dihydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl,tetrahydrofuranyl, tetrahydrotriazinyl, tetrahydropyrazolyl,tetrahydrooxazinyl, tetrahydropyrimidinyl, octahydrobenzofuranyl,octahydrobenzimidazolyl, octahydrobenzothiazolyl, imidazolidinyl,pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl,pyrazolidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiazinyl,tetrahydrothiadiazinyl, tetrahydro-oxazolyl, morpholinyl, oxetanyl,tetrahydrodiazinyl, oxazinyl, oxathiazinyl, quinuclidinyl, chromanyl,isochromanyl, dihydrobenzodioxinyl, benzodioxolyl, benzoxazinyl,indolinyl, dihydrobenzofuranyl, tetrahydroquinolyl, isochromyl,dihydro-1H-isoindolyl, 2-azabicyclo[2.2.1]heptanonyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl and the like.Further examples of heterocycloalkyl rings include tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, imidazolidin-1-yl, imidazolidin-2-yl,imidazolidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl,piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl,piperazin-1-yl, piperazin-2-yl, 1,3-oxazolidin-3-yl, 1,4-oxazepan-1-yl,isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl,1,2-tetrahydrothiazin-2-yl, 1,3-thiazinan-3-yl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-4-yl,oxazolidinonyl, 2-oxo-piperidinyl (e.g., 2-oxo-piperidin-1-yl), and thelike.

The term “optionally substituted heterocycloalkyl” [e.g., optionallysubstituted (4- to 10-membered)heterocycloalkyl] refers to aheterocycloalkyl, as defined above, in which one or more hydrogen atoms,where chemically permissible, are replaced by a substituent selectedfrom the group consisting of halogen, oxo, cyano, hydroxy, —SF₅, nitro,—N(R⁴)(R⁵), —N(R⁴)(C(═O)R⁵), —N(R⁴)C(═O)—OR⁵, —C(═O)—N(R⁴)(R⁵),—C(═O)—O—N(R⁴)(R⁵), —C(═O)—R⁴, —C(═O)—OR⁴, and (C₃-C₈)cycloalkyl, inwhich R⁴ and R⁵ are each independently hydrogen or optionallysubstituted (C₁-C₆)alkyl.

A “(C₆-C₁₀)aryl” refers to an all-carbon monocyclic or fused-ringpolycyclic aromatic group having a conjugated pi-electron systemcontaining from 6 to 10 carbon atoms, such as phenyl or naphthyl.

The term “optionally substituted (C₆-C₁₀)aryl” refers to a (C₆-C₁₀)aryl,as defined above, in which one or more hydrogen atoms are replaced by asubstituent selected from the group consisting of halogen, cyano,hydroxy, —SF₅, nitro, —N(R⁴)(R⁵), —N(R⁴)(C(═O)R⁵), —N(R⁴)C(═O)—OR⁵,—C(═O)—N(R⁴)(R⁵), —C(═O)—O—N(R⁴)(R⁵), —C(═O)—R⁴, —C(═O)—OR⁴, and(C₃-C₈)cycloalkyl, in which R⁴ and R⁵ are each independently hydrogen oroptionally substituted (C₁-C₆)alkyl.

As used herein, the term “heteroaryl” refers to monocyclic or fused-ringpolycyclic aromatic heterocyclic groups with one or more heteroatom ringmembers (ring-forming atoms) each independently selected from oxygen(O), sulfur (S) and nitrogen (N) in at least one ring. A “(5- to14-membered)heteroaryl” ring refers to a heteroaryl ring having from 5to 14 ring atoms in which at least one of the ring atoms is a heteroatom(i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms beingindependently selected from the group consisting of carbon, oxygen,nitrogen, and sulfur. A “(5- to 10-membered)heteroaryl” ring refers to aheteroaryl ring having from 5 to 10 ring atoms in which at least one ofthe ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), withthe remaining ring atoms being independently selected from the groupconsisting of carbon, oxygen, nitrogen, and sulfur. A “(5- to10-membered)nitrogen-containing heteroaryl” ring refers to a heteroarylring having from 5 to 10 ring atoms in which at least one of the ringatoms is nitrogen, with the remaining ring atoms being independentlyselected from the group consisting of carbon and nitrogen. A “(5- to6-membered)heteroaryl” refers to a heteroaryl ring having from 5 to 6ring atoms in which at least one of the ring atoms is a heteroatom(i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms beingindependently selected from the group consisting of carbon, oxygen,nitrogen, and sulfur. A “(5- to 6-membered)nitrogen-containingheteroaryl” refers to a heteroaryl ring having from 5 to 6 ring atoms inwhich all of the heteroatoms in the ring are nitrogen. A“(6-membered)nitrogen-containing heteroaryl” refers to a heteroaryl ringhaving 6 ring atoms in which all of the heteroatoms in the ring arenitrogen. A “(5-membered)nitrogen-containing heteroaryl” refers to aheteroaryl ring having 5 ring atoms in which all of the heteroatoms inthe ring are nitrogen. A heteroaryl may be a single ring or 2 or 3 fusedrings. Examples of heteroaryls include, but are not limited to,6-membered ring substituents such as pyridinyl, pyrazinyl, pyrimidinyland pyridazinyl; 5-membered heteroaryls such as triazolyl, imidazolyl,furanyl, isoxazolyl, isothiazolyl, 1,2,3-, 1,2,4, 1,2,5-, or1,3,4-oxadiazolyl, oxazolyl, thiophenyl, thiazolyl, isothiazolyl, andpyrazolyl; 6/5-membered fused ring substituents such as indolyl,indazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxadiazolyl,benzothiazolyl, isobenzothiofuranyl, benzothiofuranyl, benzisoxazolyl,benzoxazolyl, benzodioxolyl, furanopyridinyl, purinyl, imidazopyridinyl,imidazopyrimidinyl, pyrrolopyridinyl, pyrazolopyridinyl,pyrazolopyrimidinyl, thienopyridinyl, triazolopyrimidinyl,triazolopyridinyl (e.g.,5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-2-yl), and anthranilyl;and 6/6-membered fused ring substituents such as quinolinyl,isoquinolinyl, cinnolinyl, quinazolinyl, oxochromanyl, and1,4-benzoxazinyl.

It is to be understood that the heteroaryl may be optionally fused to acycloalkyl group, or to a heterocycloalkyl group, as defined herein.

The heteroaryl substituent may be attached to the imidazopyridazine coreof the compounds of the present invention via a nitrogen atom having theappropriate valence, or via any ring carbon atom or to the nitrogen ofthe amide moiety on the imidazopyridazine core. The heteroaryl moietymay be optionally substituted with one or more substituents at anitrogen atom having the appropriate valence, or at any available carbonatom.

The terms “optionally substituted (5- to 14-membered)heteroaryl”,“optionally substituted (5- to 6-membered)heteroaryl” and “optionallysubstituted (5- to 6-membered)nitrogen-containing heteroaryl” refer to a(5- to 14-membered)heteroaryl, a (5- to 6-membered)heteroaryl, and a (5-to 6-membered)nitrogen-containing heteroaryl, as defined above, in whichone or more hydrogen atoms are replaced, where chemically permissible,by a substituent selected from the group consisting of halogen, oxo,cyano, hydroxy, —SF₅, nitro, —N(R⁴)(R⁵), —N(R⁴)(C(═O)R⁵),—N(R⁴)C(═O)—OR⁵, —C(═O)—N(R⁴)(R⁵), —C(═O)—O—N(R⁴)(R⁵), —C(═O)—R⁴,—C(═O)—OR⁴, and (C₃-C₈)cycloalkyl, in which R⁴ and R⁵ are eachindependently hydrogen or optionally substituted (C₁-C₆)alkyl. Thesubstituent can be attached to the heteroaryl moiety at any availablecarbon atom or to a heteroatom when the heteroatom is nitrogen havingthe appropriate valence.

“halo” or “halogen”, as used herein, refers to a chlorine, fluorine,bromine, or iodine atom.

“hydroxy” or “hydroxyl”, as used herein, means an —OH group.

“cyano”, as used herein, means a —CN group, which also may be depicted:

“nitro”, as used herein, means an —NO₂ group.

“oxo”, as used herein, means a ═O moiety. When an oxo is substituted ona carbon atom, they together form a carbonyl moiety [—C(═O)—]. When anoxo is substituted on a sulfur atom, they together form a sulfoxidemoiety [—S(═O)—]; when two oxo groups are substituted on a sulfur atom,they together form a sulfonyl moiety [—S(═O)₂—].

“Optionally substituted”, as used herein, means that substitution isoptional and therefore includes both unsubstituted and substituted atomsand moieties. A “substituted” atom or moiety indicates that any hydrogenon the designated atom or moiety can be replaced with a selection fromthe indicated substituent group (up to and including that every hydrogenatom on the designated atom or moiety is replaced with a selection fromthe indicated substituent group), provided that the normal valency ofthe designated atom or moiety is not exceeded, and that the substitutionresults in a stable compound. For example, if a methyl group (i.e.,—CH₃) is optionally substituted, then up to 3 hydrogen atoms on thecarbon atom can be replaced with substituent groups.

As used herein, unless specified, the point of attachment of asubstituent can be from any suitable position of the substituent. Forexample, pyridinyl (or pyridyl) can be 2-pyridinyl (or pyridin-2-yl),3-pyridinyl (or pyridin-3-yl), or 4-pyridinyl (or pyridin-4-yl).

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any of thering-forming atoms in that ring that are substitutable (i.e., bonded toone or more hydrogen atoms). For example, as shown in Formula I above,R³ may be bonded to any ring-forming atom of the pyridazine ring that issubstitutable.

“Therapeutically effective amount” refers to that amount of the compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disorder being treated.

“Patient” refers to warm-blooded animals such as, for example, pigs,cows, chickens, horses, guinea pigs, mice, rats, gerbils, cats, rabbits,dogs, monkeys, chimpanzees, and humans.

“Treating” or “treat”, as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined immediately above. The term “treating” alsoincludes adjuvant and neo-adjuvant treatment of a subject.

“Pharmaceutically acceptable” indicates that the substance orcomposition must be compatible, chemically and/or toxicologically, withthe other ingredients comprising a formulation, and/or the mammal beingtreated therewith.

“Isoform” means any of several different forms of the same protein.

“Isozyme” or “isoenzyme” means a closely related variant of an enzymethat differs in amino acid sequence but catalyzes the same chemicalreaction.

“Isomer” means “stereoisomer” and “geometric isomer” as defined below.

“Stereoisomer” refers to compounds that possess one or more chiralcenters, which may each exist in the R or S configuration. Stereoisomersinclude all diastereomeric, enantiomeric and epimeric forms as well asracemates and mixtures thereof.

“Geometric isomer” refers to compounds that may exist in cis, trans,anti, entgegen (E), and zusammen (Z) forms as well as mixtures thereof.

This specification uses the terms “substituent,” “radical,” and “group”interchangeably.

If substituents are described as being “independently selected” from agroup, each instance of a substituent is selected independent of anyother. Each substituent therefore may be identical to or different fromthe other substituent(s).

As used herein the term “Formula I” may be hereinafter referred to as a“compound(s) of the invention.” Such terms are also defined to includeall forms of the compound of the invention including hydrates, solvates,isomers, crystalline and non-crystalline forms, isomorphs, polymorphs,and metabolites thereof. For example, the compounds of the invention, orpharmaceutically acceptable salts thereof, may exist in unsolvated andsolvated forms. When the solvent or water is tightly bound, the complexwill have a well-defined stoichiometry independent of humidity. When,however, the solvent or water is weakly bound, as in channel solvatesand hygroscopic compounds, the water/solvent content will be dependenton humidity and drying conditions. In such cases, non-stoichiometry willbe the norm.

The compounds of the invention may exist as clathrates or othercomplexes. Included within the scope of the invention are complexes suchas clathrates, drug-host inclusion complexes wherein the drug and hostare present in stoichiometric or non-stoichiometric amounts. Alsoincluded are complexes of the compounds of the invention containing twoor more organic and/or inorganic components, which may be instoichiometric or non-stoichiometric amounts. The resulting complexesmay be ionized, partially ionized, or non-ionized. For a review of suchcomplexes, see J. Pharm. Sci., 64 (8), 1269-1288 by Haleblian (August1975).

Some of the compounds of the invention have asymmetric carbon atoms. Thecarbon-carbon bonds of the compounds of the invention may be depictedherein using a solid line (-), a solid wedge (

), or a dotted wedge (

). The use of a solid line to depict bonds to asymmetric carbon atoms ismeant to indicate that all possible stereoisomers (e.g., specificenantiomers, racemic mixtures, etc.) at that carbon atom are included.The use of either a solid or dotted wedge to depict bonds to asymmetriccarbon atoms is meant to indicate that the stereoisomer shown ispresent. When present in racemic compounds, solid and dotted wedges areused to define relative stereochemistry, rather than absolutestereochemistry. Racemic compounds possessing such indicated relativestereochemistry are marked with (+/−). Unless stated otherwise, it isintended that the compounds of the invention can exist as stereoisomers,which include cis and trans isomers, optical isomers such as R and Senantiomers, diastereomers, geometric isomers, rotational isomers,conformational isomers, atropisomers, and mixtures thereof (such asracemates and diastereomeric pairs). The compounds of the invention mayexhibit more than one type of isomerism. Also included are acid additionor base addition salts wherein the counterion is optically active, forexample, D-lactate or L-lysine, or racemic, for example, DL-tartrate orDL-arginine.

When any racemate crystallizes, crystals of two different types arepossible. The first type is the racemic compound (true racemate)referred to above wherein one homogeneous form of crystal is producedcontaining both enantiomers in equimolar amounts. The second type is theracemic mixture or conglomerate wherein two forms of crystal areproduced in equimolar amounts each comprising a single enantiomer.

The compounds of this invention may be used in the form of salts derivedfrom inorganic or organic acids. Depending on the particular compound, asalt of the compound may be advantageous due to one or more of thesalt's physical properties, such as enhanced pharmaceutical stability indiffering temperatures and humidities, or a desirable solubility inwater or oil. In some instances, a salt of a compound also may be usedas an aid in the isolation, purification, and/or resolution of thecompound.

Where a salt is intended to be administered to a patient (as opposed to,for example, being used in an in vitro context), the salt preferably ispharmaceutically acceptable. The term “pharmaceutically acceptable salt”refers to a salt prepared by combining a compound of the presentinvention with an acid whose anion, or a base whose cation, is generallyconsidered suitable for mammalian consumption. Pharmaceuticallyacceptable salts are particularly useful as products of the methods ofthe present invention because of their greater aqueous solubilityrelative to the parent compound.

Suitable pharmaceutically acceptable acid addition salts of thecompounds of the present invention when possible include those derivedfrom inorganic acids, such as, but not limited to, hydrochloric,hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric,meta-phosphoric, nitric, carbonic, sulfonic, and sulfuric acids, andorganic acids such as acetic, benzenesulfonic, benzoic, citric,ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic,lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic,succinic, toluenesulfonic, tartaric, and trifluoroacetic acids. Suitableorganic acids generally include but are not limited to aliphatic,cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, andsulfonic classes of organic acids.

Specific examples of suitable organic acids include but are not limitedto acetate, trifluoroacetate, formate, propionate, succinate, glycolate,gluconate, digluconate, lactate, malate, tartrate, citrate, ascorbate,glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate,benzoate, anthranilate, stearate, salicylate, p-hydroxybenzoate,phenylacetate, mandelate, embonate (pamoate), methanesulfonate,ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate,2-hydroxyethanesulfonate, sufanilate, cyclohexylamino-ethansulfonate,algenic acid, β-hydroxybutyric acid, galactarate, galacturonate,adipate, alginate, butyrate, camphorate, camphorsulfonate,cyclopentanepropionate, dodecylsulfate, glycoheptanoate,glycerophosphate, heptanoate, hexanoate, nicotinate,2-naphthalene-sulfonate, oxalate, palmoate, pectinate,3-phenylpropionate, picrate, pivalate, thiocyanate, and undecanoate.

Furthermore, where the compounds of the invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof may includealkali metal salts, e.g., sodium or potassium salts; alkaline earthmetal salts, e.g., calcium or magnesium salts; and salts formed withsuitable organic ligands, e.g., quaternary ammonium salts. In anotherembodiment, base salts are formed from bases which form non-toxic salts,including aluminum, arginine, benzathine, choline, diethylamine,diolamine, glycine, lysine, meglumine, olamine, tromethamine and zincsalts.

Organic salts may be made from secondary, tertiary or quaternary aminesalts, such as tromethamine, diethylamine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine), and procaine. Basic nitrogen-containing groups maybe quaternized with agents such as lower alkyl (C₁-C₆) halides (e.g.,methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides),dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamylsulfates), long chain halides (e.g., decyl, lauryl, myristyl, andstearyl chlorides, bromides, and iodides), arylalkyl halides (e.g.,benzyl and phenethyl bromides), and others.

In one embodiment, hemisalts of acids and bases may also be formed, forexample, hemisulfate and hemicalcium salts.

Certain compounds of the invention may exist as geometric isomers. Thecompounds of the invention may possess one or more asymmetric centers,thus existing as two, or more, stereoisomeric forms. The presentinvention includes all the individual stereoisomers and geometricisomers of the compounds of the invention and mixtures thereof.Individual enantiomers can be obtained by chiral separation or using therelevant enantiomer in the synthesis.

In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention. The compounds may also exist in one or morecrystalline states, i.e., polymorphs, or they may exist as amorphoussolids. All such forms are encompassed by the claims.

Also within the scope of the present invention are so-called “prodrugs”of the compound of the invention. Thus, certain derivatives of thecompound of the invention that may have little or no pharmacologicalactivity themselves can, when administered into or onto the body, beconverted into the compound of the invention having the desiredactivity, for example, by hydrolytic cleavage. Such derivatives arereferred to as “prodrugs.” Further information on the use of prodrugsmay be found in “Pro-drugs as Novel Delivery Systems, Vol. 14, ACSSymposium Series (T. Higuchi and W. Stella) and “Bioreversible Carriersin Drug Design,” Pergamon Press, 1987 (ed. E. B. Roche, AmericanPharmaceutical Association). Prodrugs in accordance with the inventioncan, for example, be produced by replacing appropriate functionalitiespresent in the compounds of the present invention with certain moietiesknown to those skilled in the art as “pro-moieties” as described, forexample, in “Design of Prodrugs” by H. Bundgaard (Elsevier, 1985).

This invention also encompasses compounds of the invention containingprotective groups. One skilled in the art will also appreciate thatcompounds of the invention can also be prepared with certain protectinggroups that are useful for purification or storage and can be removedbefore administration to a patient. The protection and deprotection offunctional groups is described in “Protective Groups in OrganicChemistry”, edited by J. W. F. McOmie, Plenum Press (1973) and“Protective Groups in Organic Synthesis”, 3rd edition, T. W. Greene andP. G. M. Wuts, Wiley-Interscience (1999).

The present invention also includes all pharmaceutically acceptableisotopically labeled compounds, which are identical to those recitedherein, wherein one or more atoms are replaced by an atom having thesame atomic number, but an atomic mass or mass number different from theatomic mass or mass number which predominates in nature. Examples ofisotopes suitable for inclusion in the compounds of the presentinvention include, but are not limited to, isotopes of hydrogen, such as²H, ³H; carbon, such as ¹¹C, ¹³C, and ¹⁴C; chlorine, such as ³⁶Cl;fluorine, such as ¹⁸F; iodine, such as ¹²³I and ¹²⁵I; nitrogen, such as¹³N and ¹⁵N; oxygen, such as ¹⁵O, ¹⁷O, and ¹⁸O; phosphorus, such as ³²P;and sulfur, such as ³⁵S. Certain isotopically-labeled compounds of thepresent invention, for example, those incorporating a radioactiveisotope, are useful in drug and/or substrate tissue distribution studies(e.g., assays). The radioactive isotopes tritium, i.e., ³H, andcarbon-14, i.e., ¹⁴C, are particularly useful for this purpose in viewof their ease of incorporation and ready means of detection.Substitution with heavier isotopes such as deuterium, i.e., ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements and, hence, may be preferred in some circumstances.Substitution with positron-emitting isotopes, such as ¹¹C, ¹⁵F, ¹⁸F, ¹⁵Oand ¹³N, can be useful in positron emission tomography (PET) studies forexamining substrate receptor occupancy. Isotopically labeled compoundsof the present invention can generally be prepared by conventionaltechniques known to those skilled in the art or by processes analogousto those described in the accompanying Schemes and/or in the Examplesand Preparations using an appropriate isotopically labeled reagent inplace of the non-labeled reagent previously employed. Pharmaceuticallyacceptable solvates in accordance with the invention include thosewherein the solvent of crystallization may be isotopically substituted,e.g., D₂O, acetone-d₆, or DMSO-d₆. Compounds of the invention, whichinclude compounds exemplified in Examples 1-104 described below, includeisotopically labeled versions of these compounds, such as, but notlimited to, the deuterated and tritiated isotopes and all other isotopesdiscussed above.

Compounds

The compounds of Formula I, as described above, contain animidazo[1,2-b]pyridazine core wherein the core is substituted at the3-position by an R¹ moiety that is optionally substituted with one tothree R²; optionally substituted at the 5-, 6- and/or 7-positions by anR³ moiety; and the nitrogen of the amide moiety attached to the2-position of the imidazo[1,2-b]pyridazine core is substituted with R⁶and R⁷.

In one embodiment, in Formula I as described above, m is 0 and R¹ is a(4- to 10-membered)heterocycloalkyl optionally substituted with one tothree R².

In certain embodiments, when R¹ is an optionally substituted (4- to10-membered)heterocycloalkyl, the heterocycloalkyl is selected from thegroup consisting of azetidinyl, dihydrofuranyl, dihydrothiophenyl,tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydrotriazinyl,tetrahydropyrazolyl, tetrahydrooxazinyl, tetrahydropyrimidinyl,octahydrobenzofuranyl, octahydrobenzimidazolyl,octaohydrobenzothiazolyl, imidazolidinyl, pyrrolidinyl, piperidinyl,piperazinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl,pyrazolidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiazinyl,tetrahydrothiadiazinyl, tetrahydrooxazolyl, morpholinyl, oxetanyl,tetrahydrodiazinyl, dihydrooxazinyl, oxathiazinyl, quinuclidinyl,chromanyl, isochromanyl, dihydrobenzodioxinyl, benzodioxolyl,benzoxazinyl, indolinyl, dihydrobenzofuranyl, tetrahydroquinolyl,isochromanyl, dihydro-1H-isoindolyl, 2-azabicyclo[2.2.1]heptanonyl,3-azabicyclo[3.1.0]hexanyl, and 3-azabicyclo[4.1.0]heptanyl.

In certain other embodiments, when R¹ is an optionally substituted (4-to 10-membered)heterocycloalkyl, the heterocycloalkyl is selected fromdihydrobenzofuranyl, benzodioxolyl, or dihydrobenzodioxinyl.

In another embodiment, in Formula I as described above, R¹ is a(C₆-C₁₀)aryl optionally substituted with one to three R².

In certain embodiments, when R¹ is an optionally substituted(C₆-C₁₀)aryl the aryl is selected from phenyl or naphthyl.

In certain other embodiments, when R¹ is an optionally substituted(C₆-C₁₀)aryl the aryl is phenyl.

In another embodiment, in Formula I as described above, R¹ is a (5- to14-membered)heteroaryl optionally substituted with one to three R².

In certain embodiments, R¹ is an optionally substituted (5- to10-membered)heteroaryl.

In certain other embodiments, when R¹ is an optionally substituted (5-to 10-membered)heteroaryl, the heteroaryl is selected from the groupconsisting of triazolyl, imidazolyl, furanyl, isoxazolyl, isothiazolyl,1,2,3-, 1,2,4, 1,2,5-, or 1,3,4-oxadiazolyl, oxazolyl, thiophenyl,thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl,pyridazinyl, indolyl, indazolyl, benzofuranyl, benzimidazolyl,benzothienyl, benzoxadiazolyl, benzothiazolyl, isobenzothiofuranyl,benzothiofuranyl, benzisoxazolyl, benzoxazolyl, benzodioxolyl,furanopyridinyl, purinyl, imidazopyridinyl, imidazopyrimidinyl,pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl,thienopyridinyl, triazolopyrimidinyl, triazolopyridinyl, quinolinyl,isoquinolinyl, cinnolinyl, quinazolinyl, oxochromenyl, and1,4-benzoxazinyl.

In certain other embodiments, R¹ is an optionally substituted (5- to10-membered)nitrogen-containing heteroaryl. For example, when R¹ is anoptionally substituted (5- to 10-membered)nitrogen-containingheteroaryl, the heteroaryl is selected from triazolyl, imidazolyl,pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl,indazolyl, benzimidazolyl, purinyl, imidazopyridinyl,imidazopyrimidinyl, pyrrolopyridinyl, triazolopyrimidinyl,triazolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, quinolinyl,cinnolinyl, quinazolinyl, isoquinolinyl, or quinoxalinyl.

In certain other embodiments, when R¹ is an optionally substituted (5-to 10-membered)nitrogen-containing heteroaryl, the heteroaryl isselected from triazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl,pyrimidinyl, pyridazinyl, triazolopyridinyl, pyrazolopyridinyl,pyrazolopyrimidinyl, or quinoxalinyl.

In certain other embodiments, R¹ is an optionally substituted(6-membered)nitrogen-containing heteroaryl. For example, when R¹ is anoptionally substituted (6-membered)nitrogen-containing heteroaryl, theheteroaryl is selected from pyridinyl, pyrazinyl, pyrimidinyl orpyridazinyl.

In certain embodiments, when R¹ is an optionally substituted(6-membered)nitrogen-containing heteroaryl, the heteroaryl is selectedfrom pyrimidinyl or pyridinyl.

In certain other embodiments, R¹ is an optionally substituted(5-membered)nitrogen-containing heteroaryl. For example, when R¹ is anoptionally substituted (5-membered)nitrogen-containing heteroaryl, theheteroaryl is selected from triazolyl, imidazolyl, or pyrazolyl.

In any of the preceding embodiments, where chemically permissible, whenR¹ is substituted with one to three R², each R² is independentlyselected from the group consisting of halogen, oxo, cyano, hydroxy,optionally substituted (C₁-C₆)alkyl, and optionally substituted(C₁-C₆)alkoxy.

In certain embodiments, when R² is a halogen, the halogen is selectedfrom fluoro and chloro.

In certain other embodiments, when R² is an optionally substituted(C₁-C₆)alkyl, the alkyl is selected from methyl, ethyl or propyl, andthe methyl, ethyl and propyl are optionally substituted with one tothree fluorine atoms. For example, an optionally substituted alkylincludes, but is not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and thelike.

In yet another embodiment, when R² is an optionally substituted(C₁-C₆)alkoxy, the alkoxy is selected from methoxy, ethoxy or propoxyand the methoxy, ethoxy and propoxy are optionally substituted with oneto three fluorine atoms. For example, an optionally substituted alkoxyincludes, but is not limited to, fluoromethoxy, difluoromethoxy,trifluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, and thelike.

It is to be understood that any of the above-mentioned subgenuses of R¹can be combined together with any of the embodiments for R³, R⁶ and R⁷as described above and hereinafter. For example, in one embodiment, whenR¹ is an optionally substituted (C₆-C₁₀)aryl and the aryl is phenyl, bcan be 0 (R³ is absent); and one of R⁶ and R⁷ can be hydrogen and theother an optionally substituted (C₃-C₈)cycloalkyl, such as cyclopropyl.

In another embodiment, in Formula I as described above, n is an integerselected from 0, 1, or 2; and R⁶ and R⁷ are each independently selectedfrom the group consisting of hydrogen, optionally substituted(C₁-C₆)alkyl, —(CH₂)_(n)—(C₃-C₈)cycloalkyl, —(CH₂)_(n)—(C₆-C₁₀)aryl, and—(CH₂)_(n)—(5- to 6-membered)heteroaryl, and where chemicallypermissible, the (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, and (5- to6-membered)heteroaryl are optionally substituted with one to three R⁸;or

R⁶ and R⁷ taken together with the nitrogen to which they are attachedform a (4- to 6-membered)heterocycloalkyl, and where chemicallypermissible, the (4- to 6-membered)-heterocycloalkyl is optionallysubstituted with one to three R⁹;

when present, each R⁸ is independently selected from the groupconsisting of halogen, oxo, cyano, hydroxy, —SF₅, nitro, optionallysubstituted (C₁-C₆)alkyl, optionally substituted (C₂-C₆)alkenyl,optionally substituted (C₂-C₆)alkynyl, optionally substituted(C₁-C₆)alkylthio, optionally substituted (C₁-C₆)alkoxy, —N(R⁴)(R⁵),—N(R⁴)(C═(O)R⁵), —C(═O)N(R⁴)(R⁵), —C(═O)—O—N(R⁴)(R⁵), —C(═O)—R⁴, and—C(═O)—OR⁴; and

when present, each R⁹ is independently selected from the groupconsisting of halogen, oxo, cyano, hydroxy, —SF₅, nitro, optionallysubstituted (C₁-C₆)alkyl, optionally substituted (C₂-C₆)alkenyl,optionally substituted (C₂-C₆)alkynyl, optionally substituted(C₁-C₆)alkylthio, optionally substituted (C₁-C₆)alkoxy, —N(R⁴)(R⁵),—N(R⁴)(C═(O)R⁵), —C(═O)N(R⁴)(R⁵), —C(═O)—O—N(R⁴)(R⁵), —C(═O)—R⁴, and—C(═O)—OR⁴.

In certain embodiments, in Formula I as described above, one of R⁶ andR⁷ is hydrogen and the other is an optionally substituted (C₁-C₆)alkyl.

In certain embodiments, when one of R⁶ and R⁷ is an optionallysubstituted (C₁-C₆)alkyl, the alkyl is selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,pentyl and hexyl, wherein the methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, pentyl and hexyl are optionally substituted with one or morefluorine atoms.

In certain other embodiments, when one of R⁶ and R⁷ is an optionallysubstituted (C₁-C₆)alkyl, the alkyl is selected from methyl, ethyl orpropyl and the methyl, ethyl and propyl are optionally substituted withone to three fluorine atoms. For example, the optionally substituted(C₁-C₆)alkyl is selected from fluoromethyl, difluoromethyl,trifluoromethyl, fluoroethyl, difluoroethyl, or trifluoroethyl.

In another embodiment, in Formula I as described above; n is an integerselected from 0, 1, or 2; and one of R⁶ and R⁷ is hydrogen and the otheris —(CH₂)_(n)—(C₃-C₈)cycloalkyl, wherein the cycloalkyl is optionallysubstituted with one to three R⁸.

In certain embodiments, when one of R⁶ and R⁷ is an optionallysubstituted (C₃-C₈)cycloalkyl, the cycloalkyl is selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl orbicyclo[1.1.1]pentyl.

In certain embodiments, when one of R⁶ and R⁷ is an optionallysubstituted (C₃-C₈)cycloalkyl, the cycloalkyl is selected fromcyclopropyl or bicyclo[1.1.1]pentyl.

In certain embodiments, when one of R⁶ and R⁷ is an optionallysubstituted (C₃-C₈)cycloalkyl, the cycloalkyl is cyclopropyl.

In another embodiment, in Formula I as described above; n is selectedfrom 0, 1, or 2; and one of R⁶ and R⁷ is hydrogen and the other is—(CH₂)_(n)—(C₆-C₁₀)aryl, wherein the aryl is optionally substituted withone to three R⁸.

In certain embodiments, when one of R⁶ and R⁷ is an optionallysubstituted (C₆-C₁₀)aryl the (C₆-C₁₀)aryl is selected from phenyl ornaphthyl.

In certain embodiments, when one of R⁶ and R⁷ is an optionallysubstituted (C₆-C₁₀)aryl the (C₆-C₁₀)aryl is phenyl.

In another embodiment, in Formula I as described above; one of R⁶ and R⁷is hydrogen and the other is —(CH₂)_(n)-(5- to 6-membered)heteroaryl,wherein the heteroaryl is optionally substituted with one to three R⁸.

In certain embodiments, when one of R⁶ and R⁷ is an optionallysubstituted (5- to 6-membered)heteroaryl, the heteroaryl is selectedfrom triazolyl, imidazolyl, furanyl, isoxazolyl, isothiazolyl, 1,2,3-,1,2,4, 1,2,5-, or 1,3,4-oxadiazolyl, oxazolyl, thiophenyl, thiazolyl,isothiazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, orpyridazinyl.

In certain embodiments, when one of R⁶ and R⁷ is an optionallysubstituted (5- to 6-membered)heteroaryl, the heteroaryl is oxazolyl.

In certain embodiments, when one of R⁶ and R⁷ is an optionallysubstituted (5- to 6-membered)heteroaryl, the heteroaryl is a (5- to6-membered)nitrogen-containing heteroaryl.

In certain embodiments, when one of R⁶ and R⁷ is an optionallysubstituted (5- to 6-membered)nitrogen-containing heteroaryl, theheteroaryl is selected from triazolyl, imidazolyl, pyrazolyl, pyridinyl,pyrazinyl, pyrimidinyl, or pyridazinyl.

In certain embodiments, when one of R⁶ and R⁷ is an optionallysubstituted (5- to 6-membered)nitrogen-containing heteroaryl, theheteroaryl is selected from triazolyl, pyrazolyl, or pyrimidinyl.

In any of the preceding embodiments, when one of R⁶ and R⁷ is a(C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl, or (5- to 6-membered)heteroarylsubstituted with one to three R⁸, each R⁸ is independently selected fromthe group consisting of halogen, oxo, cyano, hydroxy, optionallysubstituted (C₁-C₆)alkyl, and optionally substituted (C₁-C₆)alkoxy.

In certain embodiments, when R⁸ is a halogen, the halogen is selectedfrom fluoro and chloro.

In certain other embodiments, when R⁸ is an optionally substituted(C₁-C₆)alkyl, the alkyl is selected from methyl, ethyl or propyl, andthe methyl, ethyl and propyl are optionally substituted with one tothree fluorine atoms. For example, an optionally substituted alkylincludes, but is not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and thelike.

In yet another embodiment, when R⁸ is an optionally substituted(C₁-C₆)alkoxy, the alkoxy is selected from methoxy, ethoxy or propoxyand the methoxy, ethoxy and propoxy are optionally substituted with oneto three fluorine atoms. For example, an optionally substituted alkoxyincludes, but is not limited to, fluoromethoxy, difluoromethoxy,trifluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, and thelike.

In another embodiment, in Formula I as described above, R⁶ and R⁷ takentogether with the nitrogen to which they are attached form a (4- to6-membered)heterocycloalkyl optionally substituted with one to three R⁹.

In certain embodiments, when R⁶ and R⁷ taken together with the nitrogento which they are attached form a (4- to 6-membered)heterocycloalkyl,the heterocycloalkyl is selected from azetidinyl, tetrahydropyrazolyl,tetrahydrooxazinyl, tetrahydropyrimidinyl, imidazolidinyl, piperidinyl,piperazinyl, oxazolidinyl, or pyrrolidinyl.

In certain embodiments, when R⁶ and R⁷ taken together with the nitrogento which they are attached form a (4- to 6-membered)heterocycloalkyl,the heterocycloalkyl is azetidinyl.

In any of the preceding embodiments, when R⁶ and R⁷ taken together withthe nitrogen to which they are attached form a (4- to6-membered)heterocycloalkyl substituted with one to three R⁹, each R⁹ isindependently selected from the group consisting of halogen, oxo, cyano,hydroxy, optionally substituted (C₁-C₆)alkyl, and optionally substituted(C₁-C₆)alkoxy.

In certain embodiments, when R⁹ is a halogen, the halogen is selectedfrom fluoro and chloro.

In certain other embodiments, when R⁹ is an optionally substituted(C₁-C₆)alkyl, the alkyl is selected from methyl, ethyl or propyl, andthe methyl, ethyl and propyl are optionally substituted with one tothree fluorine atoms. For example, an optionally substituted alkylincludes, but is not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and thelike.

In yet another embodiment, when R⁹ is an optionally substituted(C₁-C₆)alkoxy, the alkoxy is selected from methoxy, ethoxy or propoxyand the methoxy, ethoxy and propoxy are optionally substituted with oneto three fluorine atoms. For example, an optionally substituted alkoxyincludes, but is not limited to, fluoromethoxy, difluoromethoxy,trifluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, and thelike.

It is to be understood that any of the above-mentioned subgenuses of R⁶and R⁷ can be combined together with any of the embodiments for R¹ andR³ as described above and hereinafter. For example, in one embodiment,when one of R⁶ and R⁷ is hydrogen and the other is an optionallysubstituted (C₃-C₈)cycloalkyl, such as cyclopropyl, R¹ can be anoptionally substituted (C₆-C₁₀)aryl wherein the aryl is phenyl, and bcan be 0 (R³ is absent).

In another embodiment, in Formula I as described above, when present,each R³ is independently selected from the group consisting of halogen,cyano, hydroxy, —SF₅, nitro, optionally substituted (C₁-C₆)alkyl, andoptionally substituted (C₁-C₆)alkoxy.

In certain embodiments, when R³ is halogen, the halogen is selected fromfluoro or chloro.

In certain other embodiments, when R³ is an optionally substituted(C₁-C₆)alkyl and/or an optionally substituted (C₁-C₆)alkoxy, the(C₁-C₆)alkyl and (C₁-C₆)alkoxy are as described above in any of thepreceding embodiments.

It is to be understood that any of the above-mentioned subgenuses of R³can be combined together with any of the embodiments for R¹, R⁶ and R⁷as described above.

In another embodiment, in Formula I as described above in any of thepreceding embodiments, b is 0.

In another embodiment, selected compounds of the present invention maybe useful for treating a PDE4B-mediated disorder, comprisingadministering to a mammal (preferably a human) in need thereof atherapeutically effective amount of a compound of the inventioneffective in inhibiting PDE4B activity; more preferably, administeringan amount of a compound of the invention having improved bindingaffinity for PDE4B while at the same time possessing less inhibitoryactivity toward PDE4D.

In certain other embodiments, selected compounds of the presentinvention may exhibit a binding affinity for the PDE4B isoform.

In certain embodiments, the compounds of the present invention have anenhanced binding affinity for the PDE4B isoform over the PDE4D isoformsuch that the compounds display about a 2-fold to about a 325-foldbinding affinity for the PDE4B isoform over the PDE4D isoform. Incertain other embodiments, the compounds of the present inventiondisplay about a 5-fold to about a 50-fold binding affinity for the PDE4Bisoform over the PDE4D isoform. In certain other embodiments, thecompounds of the present invention display about a 51-fold to about a100-fold binding affinity for the PDE4B isoform over the PDE4D isoform.In certain other embodiments, the compounds of the present inventiondisplay about a 101-fold to about a 200-fold binding affinity for thePDE4B isoform over the PDE4D isoform. In certain other embodiments, thecompounds of the present invention display about a 201-fold to about a250-fold binding affinity for the PDE4B isoform over the PDE4D isoform.In certain other embodiments, the compounds of the present inventiondisplay about a 251-fold to about a 300-fold binding affinity for thePDE4B isoform over the PDE4D isoform. In certain other embodiments, thecompounds of the present invention display about a 301-fold to about a325-fold binding affinity for the PDE4B isoform over the PDE4D isoform.In certain embodiments, the compounds of the present invention displayat least about a 5-fold binding affinity for the PDE4B isoform over thePDE4D isoform. In certain embodiments, the compounds of the presentinvention display at least about a 10-fold binding affinity for thePDE4B isoform over the PDE4D isoform. In certain embodiments, thecompounds of the present invention display at least about a 20-foldbinding affinity for the PDE4B isoform over the PDE4D isoform. Incertain other embodiments, the compounds of the present inventiondisplay at least about a 40-fold binding affinity for the PDE4B isoformover the PDE4D isoform. In certain other embodiments, the compounds ofthe present invention display at least about a 50-fold binding affinityfor the PDE4B isoform over the PDE4D isoform. In certain otherembodiments, the compounds of the present invention display at leastabout a 75-fold binding affinity for the PDE4B isoform over the PDE4Disoform. In certain other embodiments, the compounds of the presentinvention display at least about a 100-fold binding affinity for thePDE4B isoform over the PDE4D isoform. In certain other embodiments, thecompounds of the present invention display at least about a 200-foldbinding affinity for the PDE4B isoform over the PDE4D isoform. Incertain other embodiments, the compounds of the present inventiondisplay at least about a 300-fold binding affinity for the PDE4B isoformover the PDE4D isoform. In certain other embodiments, the compounds ofthe present invention display up to about a 325-fold binding affinityfor the PDE4B isoform over the PDE4D isoform. The binding affinities ofthe compounds of the present invention for the PDE4B and PDE4D isoformsare shown in Table 3 of the Experimental Section below.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention, or apharmaceutically acceptable salt thereof, in admixture with at least onepharmaceutically acceptable excipient.

In yet another embodiment, administration of the compounds of thepresent invention to a patient in need thereof may also lead to adecrease in gastrointestinal discomfort such as emesis, diarrhea, andnausea, which is currently believed to be associated with administrationof compounds having binding affinity for other PDE4 isoforms, especiallythe PDE4D isoform, resulting in an increase in patient compliance aswell as overall treatment outcome.

In another embodiment, the present invention provides a method oftreating central nervous system (CNS), neuroinflammatory, metabolic,autoimmune and inflammatory diseases or disorders comprisingadministering to the mammal, particularly a human, in need of suchtreatment a therapeutically effect amount of a compound of the presentinvention, or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides the use of acompound of the present invention, or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for treating central nervoussystem (CNS), neuroinflammatory, autoimmune and inflammatory diseases ordisorders.

Pharmacology

Phosphodiesterases (PDEs) of the PDE4 family are characterized byselective, high-affinity hydrolytic degradation of the second messengercyclic nucleotide, adenosine 3′,5′-cyclic monophosphate (cAMP). ThePDE4A, PDE4B and PDE4D subtypes are known to be widely expressedthroughout the brain, with regional and intracellular distribution forthe PDE4A, PDE4B and PDE4D subtypes being distinct, whereas the PDE4Csubtype is expressed at lower levels throughout the central nervoussystem (See: Siuciak, J. A. et al., Antipsychotic profile of rolipram:efficacy in rats and reduced sensitivity in mice deficient in thephosphodiesterase-4B (PDE4B) enzyme, Psychopharmacology (2007)192:415-424). The location of the PDE4 subtypes makes them aninteresting target for exploring new treatments for central nervoussystem diseases and disorders. For example, PDE4B has been identified asa genetic susceptibility factor for schizophrenia (See: Millar, J. K. etal., Disrupted in schizophrenia 1 and phosphodiesterase 48: towards anunderstanding of psychiatric illness, J. Physiol. 584 (2007) pp.401-405).

The PDE4 inhibitor rolipram has been shown to be useful in treating orreversing Aβ-induced memory deficits via the attenuation of neuronalinflammation and apoptosis-mediated cAMP/CREB signaling; thus PDE4 is apotential target for treatment of cognitive deficits associated with AD.(See: Wang, C. et al., The phosphodiesterase-4 inhibitor rolipramreverses Aβ-induced cognitive impairment and neuroinflammatory andapoptotic responses in rats, International Journal ofNeuropsychopharmacology (2012), 15, 749-766).

PDE4 inhibitors may also possess antidepressant effects by normalizingthe cAMP cascade (See: Fujita, M. et al., Downregulation of BrainPhosphodiesterase Type IV Measured with ¹¹ C—(R)-Rolipram PositronEmission Tomography in Major Depressive Disorder, Biological Psychiatry,72, 2012, 548-554).

Furthermore, PDE4 inhibitors have been shown to possess therapeuticactivity with implications for the treatment of multiple sclerosis (See:Sun, X. et al., Rolipram promotes remyelination possibly via MEK-ERKsignal pathway in cuprizone-induced demyelination mouse, ExperimentalNeurology 2012; 237:304-311).

In view of the above, in certain embodiments, the compounds of thepresent invention have a wide range of therapeutic applications for thetreatment of conditions or diseases of the central nervous system whichinclude neurologic, neurodegenerative and/or psychiatric disorders.Neurologic, neurodegenerative and/or psychiatric disorders include butare not limited to, (1) mood [affective] disorders; (2) neurotic,stress-related and somatoform disorders including anxiety disorders; (3)disorders comprising the symptom of cognitive deficiency in a mammal,including a human; (4) disorders comprising attention deficits,executive function deficits (working memory deficits), dysfunction ofimpulse control, extrapyramidal symptoms, disorders that are based on amalfunction of basal ganglia; (5) behavioral and emotional disorderswith onset usually occurring in childhood and adolescence; (6) disordersof psychological development; (7) systemic atrophies primarily affectingthe central nervous system; (8) extrapyramidal and movement disorders;(9) behavioral syndromes associated with physiological disturbances andphysical factors; (10) disorders of adult personality and behavior; (11)schizophrenia and other psychotic disorders; (12) mental and behavioraldisorders due to psychoactive substance use; (13) sexual dysfunctioncomprising excessive sexual drive; (14) mental retardation; (15)factitious disorders, e.g., acute hallucinatory mania; (16) episodic andparoxysmal disorders, epilepsy; (17) narcolepsy; and (18) dementia.

Examples of mood [affective] disorders that can be treated according tothe present invention include, but are not limited to, bipolar disorderI, hypomania (manic and mixed form), bipolar disorder II; depressivedisorders such as single depressive episode or recurrent majordepressive disorder, chronic depression, psychotic depression, minordepressive disorder, depressive disorder with postpartum onset,depressive disorders with psychotic symptoms; persistent mood[affective] disorders such as cyclothymia, dysthymia, euthymia;premenstrual syndrome (PMS) and premenstrual dysphoric disorder.

Examples of neurotic, stress-related and somatoform disorders that canbe treated according to the present invention include, but are notlimited to, anxiety disorders, social anxiety disorder, general anxietydisorder, panic disorder with or without agoraphobia, specific phobia,social phobia, chronic anxiety disorders; obsessive compulsive disorder;reaction to severe stress and adjustment disorders, such aspost-traumatic stress disorder (PTSD), acute stress disorder; otherneurotic disorders such as depersonalization-derealization syndrome.

The phrase “cognitive deficiency” as used here in “disorders comprisingthe symptom of cognitive deficiency” refers to a subnormal functioningor a suboptimal functioning in one or more cognitive aspects such asmemory, intellect, learning and logic ability, or attention andexecutive function (working memory) in a particular individualcomparative to other individuals within the same general age population.

Examples of “disorders comprising the symptom of cognitive deficiency”that can be treated according to the present invention include, but arenot limited to, cognitive deficits primarily but not exclusively relatedto amnesia, psychosis (schizophrenia), Parkinson's disease, Alzheimer'sdisease, multi infarct dementia, senile dementia, Lewis body dementia,stroke, frontotemporal dementia, progressive supranuclear palsy,Huntington's disease, HIV disease (HIV-associated dementia), cerebraltrauma and drug abuse; mild cognitive disorder ADHD, Asperger'ssyndrome, and age-associated memory impairment; cognitive decline ordelerium post operative or in association with intensive care therapy.

Examples of disorders usually first diagnosed in infancy, childhood andadolescence that can be treated according to the present inventioninclude, but are not limited to, hyperkinetic disorders includingdisturbance of activity and attention, attention deficit/hyperactivitydisorder (ADHD), hyperkinetic conduct disorder; attention deficitdisorder (ADD); conduct disorders, including but not limited todepressive conduct disorder; tic disorders including transient ticdisorder, chronic motor or vocal tic disorder, combined vocal andmultiple motor tic disorder (Gilles de la Tourette's syndrome),substance induced tic disorders; autistic disorders; Batten disease,excessive masturbation, nail-biting, nose-picking and thumb-sucking.

Examples of disorders of psychological development that can be treatedaccording to the present invention include, but are not limited topervasive developmental disorders, including but not limited toAsperger's syndrome and Rett syndrome, autistic disorders, childhoodautism and overactive disorder associated with mental retardation andstereotyped movements, specific developmental disorder of motorfunction, specific developmental disorders of scholastic skills.

Examples of systemic atrophies primarily affecting the central nervoussystem that can be treated according to the present invention include,but are not limited to, multiple sclerosis systemic atrophies primarilyaffecting the basal ganglia including Huntington's disease, andamyotrophic lateral sclerosis.

Examples of extrapyramidal and movement disorders with malfunctionand/or degeneration of basal ganglia that can be treated according tothe present invention include, but are not limited to, Parkinson'sdisease; second Parkinsonism such as postencephalitic Parkinsonism;Parkinsonism comprised in other disorders; Niemann-Pick disease, Lewybody disease; degenerative diseases of the basal ganglia; otherextrapyramidal and movement disorders including tremor, essential tremorand drug-induced tremor, myoclonus, chorea and drug-induced chorea,drug-induced tics and tics of organic origin, drug-induced acutedystonia, drug-induced tardive dyskinesia, muscular spasms and disordersassociated with muscular spasticity or weakness including tremors;mental deficiency (including spasticity, Down syndrome and fragile Xsyndrome), L-dopa-induced dyskinesia; restless leg syndrome andStiff-man syndrome.

Further examples of movement disorders with malfunction and/ordegeneration of basal ganglia that can be treated according to thepresent invention include, but are not limited to, dystonia includingbut not limited to focal dystonia, multiple-focal or segmental dystonia,torsion dystonia, hemispheric, generalized and tardive dystonia (inducedby psychopharmacological drugs). Focal dystonia include cervicaldystonia (torticolli), blepharospasm (cramp of the eyelid), appendiculardystonia (cramp in the extremities, like the writer's cramp), ormandibular dystonia and spasmodic dysphonia (cramp of the vocal cord);neuroleptic-induced movement disorders including but not limited toneuroleptic malignant syndrome (NMS), neuroleptic-induced Parkinsonism,neuroleptic-induced early onset or acute dyskinesia, neuroleptic-inducedacute dystonia, neuroleptic-induced acute akathisia, neuroleptic-inducedtardive dyskinesia, neuroleptic-induced tremor.

Examples of behavioral syndromes associated with physiologicaldisturbances and physical factors according to the present inventioninclude, but are not limited to, nonorganic sleep disorders, includingbut not limited to nonorganic hypersomnia, nonorganic disorder of thesleep-wake schedule (circadian rhythm sleep disorder), insomnia,parasomnia and sleep deprivation; mental and behavioral disordersassociated with the puerperium including postnatal and postpartumdepression; eating disorders, including but not limited to anorexianervosa, bulimia nervosa, binge eating disorder, hyperphagia, obesity,compulsive eating disorders and pagophagia.

Examples of disorders of adult personality and behavior that can betreated according to the present invention include, but are not limitedto, personality disorders, including but not limited to emotionallyunstable, borderline, obsessive-compulsive, anankastic, dependent andpassive-aggressive personality disorder; habit and impulse disorders(impulse-control disorder) including intermittent explosive disorder,pathological gambling, pathological fire-setting (pyromania),pathological stealing (kleptomania), trichotillomania; Munchausensyndrome.

Examples of schizophrenia and other psychotic disorders that can betreated according to the present invention include, but are not limitedto, continuous or episodic schizophrenia of different types (forinstance paranoid, hebephrenic, catatonic, undifferentiated, residual,and schizophreniform disorders); schizotypal disorders (such asborderline, latent, prepsychotic, prodromal, pseudoneuroticpseudopsychopathic schizophrenia and schizotypal personality disorder);persistent delusional disorders; acute, transient and persistentpsychotic disorders; induced delusional disorders; schizoaffectivedisorders of different type (for instance manic depressive or mixedtype); puerperal psychosis and other and unspecified nonorganicpsychosis.

Examples of mental and behavioral disorders due to psychoactivesubstance use that can be treated according to the present inventioninclude, but are not limited to, mental and behavioral disorders due touse of alcohol, opioids, cannabinoids, sedatives or hypnotics, cocaine;mental and behavioral disorders due to the use of other stimulantsincluding caffeine, mental and behavioral disorders due to drugdependence and abuse (e.g., narcotic dependence, alcoholism, amphetamineand methamphetamine dependence, opioid dependence, cocaine addiction,nicotine dependence, and drug withdrawal syndrome, and relapseprevention), use of hallucinogens, tobacco (nicotine), volatile solventsand mental and behavioral disorders due to multiple drug use and use ofother psychoactive substances including the following subtype symptoms:harmful use, dependence syndrome, withdrawal state, and withdrawal statewith delirium.

Examples of dementia that can be treated according to the presentinvention include, but are not limited to, vascular dementia, dementiadue to Creutzfeld-Jacob disease, HIV, head trauma, Parkinson's,Huntington's, Pick's disease, dementia of the Alzheimer's type.

In certain embodiments, the present invention is directed to methods forthe treatment of schizophrenia by administration of a therapeuticallyeffective amount of a compound of the present invention to a patient inneed thereof.

In certain other embodiments, the invention is further directed to amethod for the treatment of cognitive impairment associated withschizophrenia by administration of a therapeutically effective amount ofa compound of the present invention to a patient in need thereof.

In addition to the central nervous system disorders mentioned above,there is extensive literature in the art describing the effects of PDEinhibitors on various autoimmune and inflammatory cell responses, whichin addition to cAMP increase, include inhibition of superoxideproduction, degranulation, chemotaxis and tumor necrosis factor (TNF)release in eosinophils, neutrophils and monocytes. Therefore, thecompounds of the present invention may be useful for treating autoimmuneand Inflammatory diseases. (See: Schett, G. et al., Apremilast: A novelPDE4 Inhibitor in the Treatment of Autoimmune and Inflammatory Diseases,Ther. Adv. Musculoskeletal Dis. 2010; 2(5):271-278). For example, thecompounds of the present invention may be useful for treatment of oralulcers associated with Behçet's disease. The compounds of the presentinvention may also be useful for the treatment of pain associated witharthritis (See: Hess, A. et al., Blockade of TNF-α rapidly inhibits painresponses in the central nervous system, PNAS, vol. 108, no. 9,3731-3736 (2011) or for the treatment of psoriasis or psoriaticarthritis (See: Schafer, P., Apremilast mechanism of action andapplication to psoriasis and psoriatic arthritis, Biochem. Pharmacol.(2012), 15; 83(12):1583-90). Accordingly, compounds of the presentinvention may also be useful for treatment of ankylosing spondylitis[see: Patan, E. et al., Efficacy and safety of apremilast, an oralphosphodiesterase 4 inhibitor, in ankylosing spondylitis, Ann. Rheum.Dis. (Sep. 14, 2102)]. Other conditions treatable by administration ofthe compounds of the present invention include, but are not limited to,acute and chronic airway diseases such as, but not limited to, asthma,chronic or acute bronchoconstriction, chronic bronchitis,bronchiectasis, small airways obstruction, emphysema, obstructive orinflammatory airways diseases, acute respiratory distress syndrome(ARDS), COPD, pneumoconiosis, seasonal allergic rhinitis or perennialallergic rhinitis or sinusitis, and acute lung injury (ALI).

In yet another embodiment, the compounds of the present invention may beuseful for treating rheumatoid arthritis, gout, and fever, edema andpain associated with inflammation, eosinophil-related disorders,dermatitis or eczema, urticaria, conjunctivitis, uveitis, psoriasis,inflammatory bowel disease, sepsis, septic shock, liver injury,pulmonary hypertension, pulmonary edema, bone loss disease, andinfection.

In yet another embodiment, the compounds of the present invention may beuseful for treating cancer. For example, the compounds of the presentinvention may be useful for treatment of brain cancer (e.g.,medulloblastoma) (See: Schmidt, A. L., BDNF and PDE4, but not GRPR,Regulate Viability of Human Medulloblastoma Cells, J. Mol. Neuroscience(2010) 40:303-310). The compounds of the present invention may also beuseful for treating melanoma (See: Marquette, A. et al., ERK and PDE4cooperate to induce RAF isoform switching in melanoma, Nature Structural& Molecular Biology, vol. 18, no. 5, 584-91, 2011). In certainembodiments, the compounds of the present invention may be useful fortreating leukemia, e.g., chronic lymphocytic leukemia, (See: Kim, D. H.et al., Type 4 Cyclic Adenosine Monophosphate Phosphodiesterase as aTherapeutic Target in Chronic Lymphocytic Leukemia, Blood Journal of TheAmerican Society of Hematology, Oct. 1, 1998, vol. 92, no. 7 2484-2494).In other embodiments, the compounds may be useful for treating brain orophthamological tumors.

In certain other embodiments, the compounds of the present invention maybe useful for treating diabetes or diseases associated with diabetes(See: Vollert, S. et al., The glucose-lowering effects of the PDE4inhibitors roflumilast and roflumilast-N-oxide in db/db mice,Diabetologia (2012) 55:2779-2788. Wouters, E. F. M. et al., Effect ofthe Phosphodiesterase 4 Inhibitor Roflumilast on Glucose Metabolism inPatients with Treatment-Naïve, Newly Diagnosed Type 2 Diabetes Mellitus,Journal of Clinical Endocrinology and Metabolism 2012, 97, 1720-1725).Other examples include, but are not limited to, diabetic maculardegeneration, diabetic neuropathy, obesity, type 2 diabetes (non-insulindependent diabetes), metabolic syndrome, glucose intolerance, urinaryincontinence (e.g., bladder overactivity), diabetic macular edema,nephropathy and related health risks, symptoms or disorders. As such,the compounds can also be used to reduce body fat or body weight of anoverweight or obese individual.

In certain other embodiments, the compounds of the present invention maybe useful in the prevention and treatment of disorders associated withenhanced endothelial activity, impaired endothelial barrier functionand/or enhanced neoangiogenesis, such as septic shock; angioedema,peripheral edema, communicating or non-communicating hydrocephalus,vascular edema, cerebral edema; reduced natriuria pathology;inflammatory diseases, including asthma, rhinitis, arthritis andrheumatoid diseases and autoimmune diseases; acute renal or liverfailure, liver dysfunction; psoriasis, Irritable Bowel Disease (IBD),Crohn's disease, and benign/malignant neoplasia.

In certain other embodiments, the compounds of the present invention maybe useful for treating diseases of the spinal cord and/or peripheralnervous system, including spinal cord injury, spinal cord edema, spinalcord tumors, vascular malformations or anomalies of the spinal cord,syringomyelia, and hydromyelia.

In certain other embodiments, the compounds described herein are furtheruseful in the prevention and treatment of disorders associated withthrombosis, embolism, or ischemic disorders including, but not limitedto, thrombosis-induced tissue infarction in coronary artery disease, incerebrovascular disease (including cerebral arteriosclerosis, cerebralamyloid angiopathy, hereditary cerebral hemorrhage, and brainhypoxia-ischemia) and/or in peripheral vascular disease; stable andunstable angina, transient ischemic attacks, stroke, atherosclerosis,myocardial infarct, cerebral infarct, reperfusion injury(brain/cardiac), traumatic brain injury, subdural, epidural orsubarachnoid hemorrhage, migraine, cluster and tension headaches,placental insufficiency, thrombosis after surgical procedures, such asbypass, angioplasty, stent placement, and heart valve replacement.

In certain other embodiments, the compounds described herein are furtheruseful for treating pain conditions and disorders. Examples of such painconditions and disorders include, but are not limited to, inflammatorypain, hyperalgesia, inflammatory hyperalgesia, migraine, cancer pain,osteoarthritis pain, post-surgical pain, non-inflammatory pain,neuropathic pain, sub-categories of neuropathic pain includingperipheral neuropathic pain syndromes, chemotherapy-induced neuropathy,complex regional pain syndrome, HIV sensory neuropathy, neuropathysecondary to tumor infiltration, painful diabetic neuropathy, phantomlimb pain, postherpetic neuralgia, postmastectomy pain, trigeminalneuralgia, central neuropathic pain syndromes, central post-stroke pain,multiple sclerosis pain, Parkinson disease pain, and spinal cord injurypain.

In certain other embodiments, the compounds described herein are furtheruseful for treating wounds (or promoting wound healing), burns,scarring, and related conditions.

In certain other embodiments, the compounds described herein are furtheruseful for treating neuronal damage disorders (including ocular damage,retinopathy including diabetic macular edema or macular degeneration ofthe eye, tinnitus, hearing impairment and loss, and brain edema).

In certain other embodiments, the compounds described herein are furtheruseful for treating transplant rejection, allograft rejection, renal andliver failure, and restless leg syndrome.

Formulations

The compounds of the invention may be administered orally. Oraladministration may involve swallowing, so that the compound enters thegastrointestinal tract, or buccal or sublingual administration may beemployed, by which the compound enters the blood stream directly fromthe mouth.

In another embodiment, the compounds of the invention may also beadministered directly into the blood stream, into muscle, or into aninternal organ. Suitable means for parenteral administration includeintravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular and subcutaneous. Suitable devices for parenteraladministration include needle (including microneedle) injectors,needle-free injectors and infusion techniques.

In another embodiment, the compounds of the invention may also beformulated such that administration topically to the skin or mucosa(i.e., dermally or transdermally) leads to systemic absorption of thecompound. In another embodiment, the compounds of the invention can alsobe formulated such that administration intranasally or by inhalationleads to systemic absorption of the compound. In another embodiment, thecompounds of the invention may be formulated such that administrationrectally or vaginally leads to systemic absorption of the compound.

The dosage regimen for the compounds and/or compositions containing thecompounds is based on a variety of factors, including the type, age,weight, sex and medical condition of the patient; the severity of thecondition; the route of administration; and the activity of theparticular compound employed. Thus the dosage regimen may vary widely.Dosage levels of the order from about 0.01 mg to about 100 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions. In one embodiment, the total daily dose of acompound of the invention (administered in single or divided doses) istypically from about 0.01 to about 100 mg/kg. In another embodiment, thetotal daily dose of the compound of the invention is from about 0.1 toabout 50 mg/kg, and in another embodiment, from about 0.5 to about 30mg/kg (i.e., mg compound of the invention per kg body weight). In oneembodiment, dosing is from 0.01 to 10 mg/kg/day. In another embodiment,dosing is from 0.1 to 1.0 mg/kg/day. Dosage unit compositions maycontain such amounts or submultiples thereof to make up the daily dose.In many instances, the administration of the compound will be repeated aplurality of times in a day (typically no greater than 4 times).Multiple doses per day typically may be used to increase the total dailydose, if desired.

For oral administration, the compositions may be provided in the form oftablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0,25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 and 500 milligrams of theactive ingredient for the symptomatic adjustment of the dosage to thepatient. A medicament typically contains from about 0.01 mg to about 500mg of the active ingredient, or in another embodiment, from about 1 mgto about 100 mg of active ingredient. Intravenously, doses may rangefrom about 0.1 to about 10 mg/kg/minute during a constant rate infusion.

Suitable subjects according to the present invention include mammaliansubjects. Mammals according to the present invention include, but arenot limited to, canine, feline, bovine, caprine, equine, ovine, porcine,rodents, lagomorphs, primates, and the like, and encompass mammals inutero. In one embodiment, humans are suitable subjects. Human subjectsmay be of either gender and at any stage of development.

In another embodiment, the invention comprises the use of one or morecompounds of the invention for the preparation of a medicament for thetreatment of the conditions recited herein.

For the treatment of the conditions referred to above, the compounds ofthe invention can be administered as compound per se. Alternatively,pharmaceutically acceptable salts are suitable for medical applicationsbecause of their greater aqueous solubility relative to the parentcompound.

In another embodiment, the present invention comprises pharmaceuticalcompositions. Such pharmaceutical compositions comprise a compound ofthe invention presented with a pharmaceutically acceptable carrier. Thecarrier can be a solid, a liquid, or both, and may be formulated withthe compound as a unit-dose composition, for example, a tablet, whichcan contain from 0.05% to 95% by weight of the active compounds. Acompound of the invention may be coupled with suitable polymers astargetable drug carriers. Other pharmacologically active substances canalso be present.

The compounds of the present invention may be administered by anysuitable route, preferably in the form of a pharmaceutical compositionadapted to such a route, and in a dose effective for the treatmentintended. The active compounds and compositions, for example, may beadministered orally, rectally, parenterally, or topically (e.g.,intranasal or ophthalmic).

Oral administration of a solid dose form may be, for example, presentedin discrete units, such as hard or soft capsules, pills, cachets,lozenges, or tablets, each containing a predetermined amount of at leastone compound of the present invention. In another embodiment, the oraladministration may be in a powder or granule form. In anotherembodiment, the oral dose form is sub-lingual, such as, for example, alozenge. In such solid dosage forms, the compounds of the presentinvention are ordinarily combined with one or more adjuvants. Suchcapsules or tablets may contain a controlled-release formulation. In thecase of capsules, tablets, and pills, the dosage forms also may comprisebuffering agents or may be prepared with enteric coatings.

In another embodiment, oral administration may be in a liquid dose form.Liquid dosage forms for oral administration include, for example,pharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs containing inert diluents commonly used in the art (e.g.,water). Such compositions also may comprise adjuvants, such as wetting,emulsifying, suspending, flavoring (e.g., sweetening), and/or perfumingagents.

In another embodiment, the present invention comprises a parenteral doseform. “Parenteral administration” includes, for example, subcutaneousinjections, intravenous injections, intraperitoneal injections,intramuscular injections, intrasternal injections, and infusion.Injectable preparations (i.e., sterile injectable aqueous or oleaginoussuspensions) may be formulated according to the known art using suitabledispersing, wetting, and/or suspending agents, and include depotformulations.

In another embodiment, the present invention comprises a topical doseform. “Topical administration” includes, for example, transdermaladministration, such as via transdermal patches or iontophoresisdevices, intraocular administration, or intranasal or inhalationadministration. Compositions for topical administration also include,for example, topical gels, sprays, ointments, and creams. A topicalformulation may include a compound that enhances absorption orpenetration of the active ingredient through the skin or other affectedareas. When the compounds of this invention are administered by atransdermal device, administration will be accomplished using a patcheither of the reservoir and porous membrane type or of a solid matrixvariety. Typical formulations for this purpose include gels, hydrogels,lotions, solutions, creams, ointments, dusting powders, dressings,foams, films, skin patches, wafers, implants, sponges, fibers, bandagesand microemulsions. Liposomes may also be used. Typical carriers includealcohol, water, mineral oil, liquid petrolatum, white petrolatum,glycerin, polyethylene glycol and propylene glycol. Penetrationenhancers may be incorporated—see, for example, Finnin and Morgan, J.Pharm. Sci., 88 (10), 955-958 (1999).

Formulations suitable for topical administration to the eye include, forexample, eye drops wherein the compound of this invention is dissolvedor suspended in a suitable carrier. A typical formulation suitable forocular or aural administration may be in the form of drops of amicronized suspension or solution in isotonic, pH-adjusted, sterilesaline. Other formulations suitable for ocular and aural administrationinclude ointments, biodegradable (e.g., absorbable gel sponges,collagen) and non-biodegradable (e.g., silicone) implants, wafers,lenses and particulate or vesicular systems, such as niosomes orliposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example,hydroxypropylmethyl cellulose, hydroxyethyl cellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum,may be incorporated together with a preservative, such as benzalkoniumchloride. Such formulations may also be delivered by iontophoresis.

For intranasal administration or administration by inhalation, theactive compounds of the invention are conveniently delivered in the formof a solution or suspension from a pump spray container that is squeezedor pumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant. Formulations suitable for intranasal administration aretypically administered in the form of a dry powder (either alone; as amixture, for example, in a dry blend with lactose; or as a mixedcomponent particle, for example, mixed with phospholipids, such asphosphatidylcholine) from a dry powder inhaler or as an aerosol sprayfrom a pressurized container, pump, spray, atomizer (preferably anatomizer using electrohydrodynamics to produce a fine mist), ornebulizer, with or without the use of a suitable propellant, such as1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. Forintranasal use, the powder may comprise a bioadhesive agent, forexample, chitosan or cyclodextrin.

In another embodiment, the present invention comprises a rectal doseform. Such rectal dose form may be in the form of, for example, asuppository. Cocoa butter is a traditional suppository base, but variousalternatives may be used as appropriate.

Other carrier materials and modes of administration known in thepharmaceutical art may also be used. Pharmaceutical compositions of theinvention may be prepared by any of the well-known techniques ofpharmacy, such as effective formulation and administration procedures.The above considerations in regard to effective formulations andadministration procedures are well known in the art and are described instandard textbooks. Formulation of drugs is discussed in, for example,Hoover, John E., Remington's Pharmaceutical Sciences, Mack PublishingCo., Easton, Pa., 1975; Liberman et al., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Kibbe et al., Eds.,Handbook of Pharmaceutical Excipients (3^(rd) Ed.), AmericanPharmaceutical Association, Washington, 1999.

The compounds of the present invention can be used, alone or incombination with other therapeutic agents, in the treatment of variousconditions or disease states. The compound(s) of the present inventionand other therapeutic agent(s) may be administered simultaneously(either in the same dosage form or in separate dosage forms) orsequentially. An exemplary therapeutic agent may be, for example, ametabotropic glutamate receptor agonist.

The administration of two or more compounds “in combination” means thatthe two compounds are administered closely enough in time that thepresence of one alters the biological effects of the other. The two ormore compounds may be administered simultaneously, concurrently orsequentially. Additionally, simultaneous administration may be carriedout by mixing the compounds prior to administration or by administeringthe compounds at the same point in time but at different anatomic sitesor using different routes of administration.

The phrases “concurrent administration,” “co-administration,”“simultaneous administration,” and “administered simultaneously” meanthat the compounds are administered in combination.

The present invention includes the use of a combination of a PDE4inhibitor compound of the present invention and one or more additionalpharmaceutically active agent(s). If a combination of active agents isadministered, then they may be administered sequentially orsimultaneously, in separate dosage forms or combined in a single dosageform. Accordingly, the present invention also includes pharmaceuticalcompositions comprising an amount of: (a) a first agent comprising acompound of the present invention or a pharmaceutically acceptable saltof the compound; (b) a second pharmaceutically active agent; and (c) apharmaceutically acceptable carrier, vehicle or diluent.

Various pharmaceutically active agents may be selected for use inconjunction with the compounds of the present invention, depending onthe disease, disorder, or condition to be treated. Pharmaceuticallyactive agents that may be used in combination with the compositions ofthe present invention include, without limitation:

(i) acetylcholinesterase inhibitors, such as donepezil hydrochloride(ARICEPT, MEMAC), physostigmine salicylate (ANTILIRIUM), physostigminesulfate (ESERINE), metrifonate, neostigmine, ganstigmine, pyridostigmine(MESTINON), ambenonium (MYTELASE), demarcarium, Debio 9902 (also knownas ZT-1; Debiopharm), rivastigmine (EXELON), ladostigil, NP-0361,galantamine hydrobromide (RAZADYNE, RIMINYL, NIVALIN), tacrine (COGNEX),tolserine, velnacrine maleate, memoquin, huperzine A (HUP-A;NeuroHitech), phenserine, edrophonium (ENLON, TENSILON), and INM-176;

(ii) amyloid-β (or fragments thereof), such as Aβ₁₋₁₅ conjugated to panHLA DR-binding epitope (PADRE), ACC-001 (Elan/Wyeth), ACI-01, ACI-24,AN-1792, Affitope AD-01, CAD106, and V-950;

(iii) antibodies to amyloid-β (or fragments thereof), such as ponezumab,solanezumab, bapineuzumab (also known as AAB-001), AAB-002 (Wyeth/Elan),ACI-01-Ab7, BAN-2401, intravenous Ig (GAMMAGARD), LY2062430 (humanizedm266; Lilly), R1450 (Roche), ACU-5A5, huC091, and those disclosed inInternational Patent Publication Nos WO04/032868, WO05/025616,WO06/036291, WO06/069081, WO06/118959, in US Patent Publication NosUS2003/0073655, US2004/0192898, US2005/0048049, US2005/0019328, inEuropean Patent Publication Nos EP0994728 and 1257584, and in U.S. Pat.No. 5,750,349;

(iv) amyloid-lowering or -inhibiting agents (including those that reduceamyloid production, accumulation and fibrillization) such as dimebon,davunetide, eprodisate, leuprolide, SK-PC-B70M, celecoxib, lovastatin,anapsos, oxiracetam, pramiracetam, varenicline, nicergoline,colostrinin, bisnorcymserine (also known as BNC), NICS-15 (Humanetics),E-2012 (Eisai), pioglitazone, clioquinol (also known as PBT1), PBT2(Prana Biotechnology), flurbiprofen (ANSAID, FROBEN) and itsR-enantiomer tarenflurbil (FLURIZAN), nitroflurbiprofen, fenoprofen(FENOPRON, NALFON), ibuprofen (ADVIL, MOTRIN, NUROFEN), ibuprofenlysinate, meclofenamic acid, meclofenamate sodium (MECLOMEN),indomethacin (INDOCIN), diclofenac sodium (VOLTAREN), diclofenacpotassium, sulindac (CLINORIL), sulindac sulfide, diflunisal (DOLOBID),naproxen (NAPROSYN), naproxen sodium (ANAPROX, ALEVE), ARC031 (ArcherPharmaceuticals), CAD-106 (Cytos), LY450139 (Lilly), insulin-degradingenzyme (also known as insulysin), the gingko biloba extract EGb-761(ROKAN, TEBONIN), tramiprosate (CEREBRIL, ALZHEMED), eprodisate(FIBRILLEX, KIACTA), compound W [3,5-bis(4-nitrophenoxy)benzoic acid],NGX-96992, neprilysin (also known as neutral endopeptidase (NEP)),scyllo-inositol (also known as scyllitol), atorvastatin (LIPITOR),simvastatin (ZOCOR), KLVFF-(EEX)3, SKF-74652, ibutamoren mesylate, BACEinhibitors such as ASP-1702, SCH-745966, JNJ-715754, AMG-0683,AZ-12304146, BMS-782450, GSK-188909, NB-533, E2609 and TTP-854; gammasecretase modulators such as ELND-007; and RAGE (receptor for advancedglycation end-products) inhibitors, such as TTP488 (Transtech) andTTP4000 (Transtech), and those disclosed in U.S. Pat. No. 7,285,293,including PTI-777;

(v) alpha-adrenergic receptor agonists, such as guanfacine (INTUNIV,TENEX), clonidine (CATAPRES), metaraminol (ARAMINE), methyldopa(ALDOMET, DOPAMET, NOVOMEDOPA), tizanidine (ZANAFLEX), phenylephrine(also known as neosynephrine), methoxamine, cirazoline, guanfacine(INTUNIV), lofexidine, xylazine, modafinil (PROVIGIL), adrafinil, andarmodafinil (NUVIGIL);

(vi) beta-adrenergic receptor blocking agents (beta blockers), such ascarteolol, esmolol (BREVIBLOC), labetalol (NORMODYNE, TRANDATE),oxprenolol (LARACOR, TRASACOR), pindolol (VISKEN), propanolol (INDERAL),sotalol (BETAPACE, SOTALEX, SOTACOR), timolol (BLOCADREN, TIMOPTIC),acebutolol (SECTRAL, PRENT), nadolol (CORGARD), metoprolol tartrate(LOPRESSOR), metoprolol succinate (TOPROL-XL), atenolol (TENORMIN),butoxamine, and SR 59230A (Sanofi);

(vii) anticholinergics, such as amitriptyline (ELAVIL, ENDEP),butriptyline, benztropine mesylate (COGENTIN), trihexyphenidyl (ARTANE),diphenhydramine (BENADRYL), orphenadrine (NORFLEX), hyoscyamine,atropine (ATROPEN), scopolamine (TRANSDERM-SCOP), scopolaminemethylbromide (PARMINE), dicycloverine (BENTYL, BYCLOMINE, DIBENT,DILOMINE), tolterodine (DETROL), oxybutynin (DITROPAN, LYRINEL XL,OXYTROL), penthienate bromide, propantheline (PRO-BANTHINE), cyclizine,imipramine hydrochloride (TOFRANIL), imipramine maleate (SURMONTIL),lofepramine, desipramine (NORPRAMIN), doxepin (SINEQUAN, ZONALON),trimipramine (SURMONTIL), and glycopyrrolate (ROBINUL);

(viii) anticonvulsants, such as carbamazepine (TEGRETOL, CARBATROL),oxcarbazepine (TRILEPTAL), phenytoin sodium (PHENYTEK), fosphenytoin(CEREBYX, PRODILANTIN), divalproex sodium (DEPAKOTE), gabapentin(NEURONTIN), pregabalin (LYRICA), topirimate (TOPAMAX), valproic acid(DEPAKENE), valproate sodium (DEPACON), 1-benzyl-5-bromouracil,progabide, beclamide, zonisamide (TRERIEF, EXCEGRAN), CP-465022,retigabine, talampanel, and primidone (MYSOLINE);

(ix) antipsychotics, such as lurasidone (LATUDA, also known as SM-13496;Dainippon Sumitomo), aripiprazole (ABILIFY), chlorpromazine (THORAZINE),haloperidol (HALDOL), iloperidone (FANAPTA), flupentixol decanoate(DEPIXOL, FLUANXOL), reserpine (SERPLAN), pimozide (ORAP), fluphenazinedecanoate, fluphenazine hydrochloride, prochlorperazine (COMPRO),asenapine (SAPHRIS), loxapine (LOXITANE), molindone (MOBAN),perphenazine, thioridazine, thiothixine, trifluoperazine (STELAZINE),ramelteon, clozapine (CLOZARIL), norclozapine (ACP-104), risperidone(RISPERDAL), paliperidone (INVEGA), melperone, olanzapine (ZYPREXA),quetiapine (SEROQUEL), talnetant, amisulpride, ziprasidone (GEODON),blonanserin (LONASEN), and ACP-103 (Acadia Pharmaceuticals);

(x) calcium channel blockers such as lomerizine, ziconotide, nilvadipine(ESCOR, NIVADIL), diperdipine, amlodipine (NORVASC, ISTIN, AMLODIN),felodipine (PLENDIL), nicardipine (CARDENE), nifedipine (ADALAT,PROCARDIA), MEM 1003 and its parent compound nimodipine (NIMOTOP),nisoldipine (SULAR), nitrendipine, lacidipine (LACIPIL, MOTENS),lercanidipine (ZANIDIP), lifarizine, diltiazem (CARDIZEM), verapamil(CALAN, VERELAN), AR-R 18565 (AstraZeneca), and enecadin;

(xi) catechol O-methyltransferase (COMT) inhibitors, such as nitecapone,tolcapone (TASMAR), entacapone (COMTAN), and tropolone;

(xii) central nervous system stimulants, such as atomoxetine,reboxetine, yohimbine, caffeine, phenmetrazine, phendimetrazine,pemoline, fencamfamine (GLUCOENERGAN, REACTIVAN), fenethylline(CAPTAGON), pipradol (MERETRAN), deanol (also known asdimethylaminoethanol), methylphenidate (DAYTRANA), methylphenidatehydrochloride (RITALIN), dexmethylphenidate (FOCALIN), amphetamine(alone or in combination with other CNS stimulants, e.g., ADDERALL(amphetamine aspartate, amphetamine sulfate, dextroamphetaminesaccharate, and dextroamphetamine sulfate)), dextroamphetamine sulfate(DEXEDRINE, DEXTROSTAT), methamphetamine (DESOXYN), lisdexamfetamine(VYVANSE), and benzphetamine (DIDREX);

(xiii) corticosteroids, such as prednisone (STERAPRED, DELTASONE),prednisolone (PRELONE), predisolone acetate (OMNIPRED, PRED MILD, PREDFORTE), prednisolone sodium phosphate (ORAPRED ODT), methylprednisolone(MEDROL); methylprednisolone acetate (DEPO-MEDROL), andmethylprednisolone sodium succinate (A-METHAPRED, SOLU-MEDROL);

(xiv) dopamine receptor agonists, such as apomorphine (APOKYN),bromocriptine (PARLODEL), cabergoline (DOSTINEX), dihydrexidine,dihydroergocryptine, fenoldopam (CORLOPAM), lisuride (DOPERGIN),terguride spergolide (PERMAX), piribedil (TRIVASTAL, TRASTAL),pramipexole (MIRAPEX), quinpirole, ropinirole (REQUIP), rotigotine(NEUPRO), SKF-82958 (GlaxoSmithKline), cariprazine, pardoprunox andsarizotan;

(xv) dopamine receptor antagonists, such as chlorpromazine,fluphenazine, haloperidol, loxapine, risperidone, thioridazine,thiothixene, trifluoperazine, tetrabenazine (NITOMAN, XENAZINE),7-hydroxyamoxapine, droperidol (INAPSINE, DRIDOL, DROPLETAN),domperidone (MOTILIUM), L-741742, L-745870, raclopride, SB-277011A,SCH-23390, ecopipam, SKF-83566, and metoclopramide (REGLAN);

(xvi) dopamine reuptake inhibitors such as bupropion, safinamide,nomifensine maleate (MERITAL), vanoxerine (also known as GBR-12909) andits decanoate ester DBL-583, and amineptine;

(xvii) gamma-amino-butyric acid (GABA) receptor agonists, such asbaclofen (LIORESAL, KEMSTRO), siclofen, pentobarbital (NEMBUTAL),progabide (GABRENE), and clomethiazole;

(xviii) histamine 3 (H3) antagonists such as ciproxifan, tiprolisant,S-38093, irdabisant, pitolisant, GSK-239512, GSK-207040, JNJ-5207852,JNJ-17216498, HPP-404, SAR-110894,trans-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]-cyclobutanecarboxamide(PF-3654746 and those disclosed in US Patent Publication NosUS2005-0043354, US2005-0267095, US2005-0256135, US2008-0096955,US2007-1079175, and US2008-0176925; International Patent Publication NosWO2006/136924, WO2007/063385, WO2007/069053, WO2007/088450,WO2007/099423, WO2007/105053, WO2007/138431, and WO2007/088462; and U.S.Pat. No. 7,115,600);

(xix) immunomodulators such as glatiramer acetate (also known ascopolymer-1; COPAXONE), MBP-8298 (synthetic myelin basic proteinpeptide), dimethyl fumarate, fingolimod (also known as FTY720),roquinimex (LINOMIDE), laquinimod (also known as ABR-215062 andSAIK-MS), ABT-874 (human anti-IL-12 antibody; Abbott), rituximab(RITUXAN), alemtuzumab (CAMPATH), daclizumab (ZENAPAX), and natalizumab(TYSABRI);

(xx) immunosuppressants such as methotrexate (TREXALL, RHEUMATREX),mitoxantrone (NOVANTRONE), mycophenolate mofetil (CELLCEPT),mycophenolate sodium (MYFORTIC), azathioprine (AZASAN, IMURAN),mercaptopurine (PURI-NETHOL), cyclophosphamide (NEOSAR, CYTOXAN),chlorambucil (LEUKERAN), cladribine (LEUSTATIN, MYLINAX),alpha-fetoprotein, etanercept (ENBREL), and4-(benzyloxy)-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-1H,1′H-2,2′-bipyrrole(also known as PNU-156804);

(xxi) interferons, including interferon beta-1a (AVONEX, REBIF) andinterferon beta-1b (BETASERON, BETAFERON);

(xxii) levodopa (or its methyl or ethyl ester), alone or in combinationwith a DOPA decarboxylase inhibitor (e.g., carbidopa (SINEMET, CARBILEV,PARCOPA), benserazide (MADOPAR), α-methyldopa, monofluromethyldopa,difluoromethyldopa, brocresine, or m-hydroxybenzylhydrazine);

(xxiii) N-methyl-D-aspartate (NMDA) receptor antagonists, such asmemantine (NAMENDA, AXURA, EBIXA), amantadine (SYMMETREL), acamprosate(CAMPRAL), besonprodil, ketamine (KETALAR), delucemine, dexanabinol,dexefaroxan, dextromethorphan, dextrorphan, traxoprodil, CP-283097,himantane, idantadol, ipenoxazone, L-701252 (Merck), lancicemine,levorphanol (DROMORAN), LY-233536 and LY-235959 (both Lilly), methadone,(DOLOPHINE), neramexane, perzinfotel, phencyclidine, tianeptine(STABLON), dizocilpine (also known as MK-801), EAB-318 (Wyeth),ibogaine, voacangine, tiletamine, riluzole (RILUTEK), aptiganel(CERESOTAT), gavestinel, and remacimide;

(xxiv) monoamine oxidase (MAO) inhibitors, such as selegiline (EMSAM),selegiline hydrochloride (I-deprenyl, ELDEPRYL, ZELAPAR),dimethylselegilene, brofaromine, phenelzine (NARDIL), tranylcypromine(PARNATE), moclobemide (AURORIX, MANERIX), befloxatone, safinamide,isocarboxazid (MARPLAN), nialamide (NIAMID), rasagiline (AZILECT),iproniazide (MARSILID, IPROZID, IPRONID), CHF-3381 (ChiesiFarmaceutici), iproclozide, toloxatone (HUMORYL, PERENUM), bifemelane,desoxypeganine, harmine (also known as telepathine or banasterine),harmaline, linezolid (ZYVOX, ZYVOXID), and pargyline (EUDATIN,SUPIRDYL);

(xxv) muscarinic receptor (particularly M1 subtype) agonists, such ascevimeline, levetiracetam, bethanechol chloride (DUVOID, URECHOLINE),itameline, pilocarpine (SALAGEN), NGX267, arecoline, L-687306 (Merck),L-689660 (Merck), furtrethonium iodide (FURAMON, FURANOL), furtrethoniumbenzensulfonate, furtrethonium p-toluenesulfonate, McN-A-343,oxotremorine, sabcomeline, AC-90222 (Acadia Pharmaceuticals), andcarbachol (CARBASTAT, MIOSTAT, CARBOPTIC);

(xxvi) neuroprotective drugs such as bosutinib, condoliase, airmoclomol,lamotrigine, perampanel, aniracetam, minaprime, riluzole,N-hydroxy-1,2,4,9-tetrahydro-3H-carbazol-3-imine, desmoteplase,anatibant, astaxanthin, neuropeptide NAP (e.g., AL-108 and AL-208; bothAllon Therapeutics), neurostrol, perampenel, ispronicline,bis(4-β-D-glucopyranosyloxybenzyl)-2-β-D-glucopyranosyl-2-isobutyltartrate(also known as dactylorhin B or DHB), formobactin, xaliproden (XAPRILA),lactacystin, dimeboline hydrochloride (DIMEBON), disufenton (CEROVIVE),arundic acid (ONO-2506, PROGLIA, CEREACT), citicoline (also known ascytidine 5′-diphosphocholine), edaravone (RADICUT), AEOL-10113 andAEOL-10150 (both Aeolus Pharmaceuticals), AGY-94806 (also known asSA-450 and Msc-1), granulocyte-colony stimulating factor (also known asAX-200), BAY-38-7271 (also known as KN-387271; Bayer AG), ancrod(VIPRINEX, ARWIN), DP-b99 (D-Pharm Ltd), HF-0220(17-β-hydroxyepiandrosterone; Newron Pharmaceuticals), HF-0420 (alsoknown as oligotropin), pyridoxal 5′-phosphate (also known as MC-1),microplasmin, S-18986, piclozotan, NP031112, tacrolimus,L-seryl-L-methionyl-L-alanyl-L-lysyl-L-glutamyl-glycyl-L-valine,AC-184897 (Acadia Pharmaceuticals), ADNF-14 (National Institutes ofHealth), stilbazulenyl nitrone, SUN-N8075 (Daiichi Suntory BiomedicalResearch), and zonampanel;

(xxvii) nicotinic receptor agonists, such as epibatidine, bupropion,CP-601927, varenicline, ABT-089 (Abbott), ABT-594, AZD-0328(AstraZeneca), EVP-6124, R3487 (also known as MEM3454; Roche/MemoryPharmaceuticals), R4996 (also known as MEM63908; Roche/MemoryPharmaceuticals), TC-4959 and TC-5619 (both Targacept), and RJR-2403;

(xxviii) norepinephrine (noradrenaline) reuptake inhibitors, such asatomoxetine (STRATTERA), doxepin (APONAL, ADAPIN, SINEQUAN),nortriptyline (AVENTYL, PAMELOR, NORTRILEN), amoxapine (ASENDIN,DEMOLOX, MOXIDIL), reboxetine (EDRONAX, VESTRA), viloxazine (VIVALAN),maprotiline (DEPRILEPT, LUDIOMIL, PSYMION), bupropion (WELLBUTRIN), andradaxafine;

(xxix) phosphodiesterase (PDE) inhibitors, including but not limited to,(a) PDE1 inhibitors (e.g., vinpocetine (CAVINTON, CERACTIN, INTELECTOL)and those disclosed in U.S. Pat. No. 6,235,742, (b) PDE2 inhibitors(e.g., erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), BAY 60-7550, andthose described in U.S. Pat. No. 6,174,884), (c) PDE3 inhibitors (e.g.,anagrelide, cilostazol, milrinone, olprinone, parogrelil, andpimobendan), (d) PDE4 inhibitors (e.g., apremilast,ibudilastroflumilast, rolipram, Ro 20-1724, ibudilast (KETAS),piclamilast (also known as RP73401), CDP840, cilomilast (ARIFLO),roflumilast, tofimilast, oglemilast (also known as GRC 3886), tetomilast(also known as OPC-6535), lirimifast, theophylline (UNIPHYL, THEOLAIR),arofylline (also known as LAS-31025), doxofylline, RPR-122818, ormesembrine), and (e) PDES inhibitors (e.g., sildenafil (VIAGRA,REVATIO), tadalafil (CIALIS), vardenafil (LEVITRA, VIVANZA), udenafil,avanafil, dipyridamole (PERSANTINE), E-4010, E-4021, E-8010, zaprinast,iodenafil, mirodenafil, DA-8159, and those disclosed in InternationalPatent Applications WO2002/020521, WO2005/049616, WO2006/120552,WO2006/126081, WO2006/126082, WO2006/126083, and WO2007/122466), (f)PDE7 inhibitors; (g) PDE8 inhibitors; (h) PDE9 inhibitors (e.g., BAY73-6691 (Bayer AG) and those disclosed in US Patent Publication NosUS2003/0195205, US2004/0220186, US2006/0111372, US2006/0106035, and U.S.Ser. No. 12/118,062 (filed May 9, 2008)), (i) PDE10 inhibitors such as2-({4-[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]phenoxy}methyl)quinolin-3(4H)-oneand SCH-1518291; and (j) PDE11 inhibitors;

(xxx) quinolines, such as quinine (including its hydrochloride,dihydrochloride, sulfate, bisulfate and gluconate salts), chloroquine,sontoquine, hydroxychloroquine (PLAQUENIL), mefloquine (LARIAM), andamodiaquine (CAMOQUIN, FLAVOQUINE);

(xxxi) β-secretase inhibitors, such as ASP-1702, SCH-745966, JNJ-715754,AMG-0683, AZ-12304146, BMS-782450, GSK-188909, NB-533, LY-2886721,E-2609, HPP-854, (+)-phenserine tartrate (POSIPHEN), LSN-2434074 (alsoknown as LY-2434074), KMI-574, SCH-745966, Ac-rER(N²-acetyl-D-arginyl-L-arginine), loxistatin (also known as E64d), andCA074Me;

(xxxii) γ-secretase inhibitors and modulators, such as BMS-708163(Avagacest), WO20060430064 (Merck), DSP8658 (Dainippon), ITI-009,L-685458 (Merck), ELAN-G, ELAN-Z,4-chloro-N-[(2S)-3-ethyl-1-hydroxypentan-2-yl]benzenesulfonamide;

(xxxiii) serotonin (5-hydroxytryptamine) 1A (5-HT_(1A)) receptorantagonists, such as spiperone, levo-pindolol, BMY 7378, NAD-299,S-(−)-UH-301, NAN 190, lecozotan;

(xxxiv) serotonin (5-hydroxytryptamine) 2C (5-HT_(2c)) receptoragonists, such as vabicaserin and zicronapine;

(xxxv) serotonin (5-hydroxytryptamine) 4 (5-HT₄) receptor agonists, suchas PRX-03140 (Epix);

(xxxvi) serotonin (5-hydroxytryptamine) 6 (5-HT₆) receptor antagonists,such as A-964324, AVI-101, AVN-211, mianserin (TORVOL, BOLVIDON,NORVAL), methiothepin (also known as metitepine), ritanserin, ALX-1161,ALX-1175, MS-245, LY-483518 (also known as SGS518; Lilly), MS-245, Ro04-6790, Ro 43-68544, Ro 63-0563, Ro 65-7199, Ro 65-7674, SB-399885,SB-214111, SB-258510, SB-271046, SB-357134, SB-699929, SB-271046,SB-742457 (GlaxoSmithKline), Lu AE58054 (Lundbeck A/S), and PRX-07034(Epix);

(xxxvii) serotonin (5-HT) reuptake inhibitors such as alaproclate,citalopram (CELEXA, CIPRAMIL), escitalopram (LEXAPRO, CIPRALEX),clomipramine (ANAFRANIL), duloxetine (CYMBALTA), femoxetine (MALEXIL),fenfluramine (PONDIMIN), norfenfluramine, fluoxetine (PROZAC),fluvoxamine (LUVOX), indalpine, milnacipran (IXEL), paroxetine (PAXIL,SEROXAT), sertraline (ZOLOFT, LUSTRAL), trazodone (DESYREL, MOLIPAXIN),venlafaxine (EFFEXOR), zimelidine (NORMUD, ZELMID), bicifadine,desvenlafaxine (PRISTIQ), brasofensine, vilazodone, cariprazine,neuralstem and tesofensine;

(xxxviii) trophic factors, such as nerve growth factor (NGF), basicfibroblast growth factor (bFGF; ERSOFERMIN), neurotrophin-3 (NT-3),cardiotrophin-1, brain-derived neurotrophic factor (BDNF), neublastin,meteorin, and glial-derived neurotrophic factor (GDNF), and agents thatstimulate production of trophic factors, such as propentofylline,idebenone, PYM50028 (COGANE; Phytopharm), and AIT-082 (NEOTROFIN);

(xxxix) Glycine transporter-1 inhibitors such as paliflutine, ORG-25935,JNJ-17305600, and ORG-26041;

(xl) AMPA-type glutamate receptor modulators such as perampanel,mibampator, selurampanel, GSK-729327,N-{(3S,4S)-4-[4-(5-cyanothiophen-2-yl)phenoxy]tetrahydro-furan-3-yl}propane-2-sulfonamide,and the like.

(xli) Janus kinase inhibitors (JAK) such as, but not limited to,tofacitinib, ruxolitinib, baricitinib, CYT387, GLPG0634, lestaurtinib,pacritinib, and TG101348.

The present invention further comprises kits that are suitable for usein performing the methods of treatment described above. In oneembodiment, the kit contains a first dosage form comprising one or moreof the compounds of the present invention and a container for thedosage, in quantities sufficient to carry out the methods of the presentinvention.

In another embodiment, the kit of the present invention comprises one ormore compounds of the invention.

The compounds of the invention, or their pharmaceutically acceptablesalts, may be prepared by a variety of methods that are analogouslyknown in the art. The reaction Scheme described below, together withsynthetic methods known in the art of organic chemistry, ormodifications and derivatizations that are familiar to those of ordinaryskill in the art, illustrate a method for preparing the compounds.Others, including modifications thereof, will be readily apparent to oneskilled in the art.

The starting materials used herein are commercially available or may beprepared by routine methods known in the art (such as those methodsdisclosed in standard reference books such as the COMPENDIUM OF ORGANICSYNTHETIC METHODS, Vol. I-XII (published by Wiley-Interscience)).Preferred methods include, but are not limited to, those describedbelow.

During any of the following synthetic sequences, it may be necessaryand/or desirable to protect sensitive or reactive groups on any of themolecules concerned. This can be achieved by means of conventionalprotecting groups, such as those described in T. W. Greene, ProtectiveGroups in Organic Chemistry, John Wiley & Sons, 1981; T. W. Greene andP. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley &Sons, 1991; and T. W. Greene and P. G. M. Wuts, Protective Groups inOrganic Chemistry, John Wiley & Sons, 1999; and T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons,2006, which are hereby incorporated by reference.

Compounds of the present invention, or the pharmaceutically acceptablesalts of said compounds or tautomers and radioisotopes, can be preparedaccording to the reaction Schemes discussed herein below. Unlessotherwise indicated, the substituents in the Schemes are defined asabove. Isolation and purification of the products is accomplished bystandard procedures, which are known to a chemist of ordinary skill.

One skilled in the art will recognize that in some cases, the compoundsin Scheme 1 will be generated as a mixture of diastereomers and/orenantiomers; these may be separated at various stages of the syntheticScheme using conventional techniques or a combination of suchtechniques, such as, but not limited to, crystallization, normal-phasechromatography, reversed phase chromatography and chiral chromatography,to afford the single enantiomers of the invention.

It will be understood by one skilled in the art that the varioussymbols, superscripts and subscripts used in the Scheme, methods andexamples are used for convenience of representation and/or to reflectthe order in which they are introduced in the Scheme, and are notintended to necessarily correspond to the symbols, superscripts orsubscripts in the appended claims. The Schemes are representative ofmethods useful in synthesizing the compounds of the present invention.They are not to constrain the scope of the invention in any way.

Scheme 1 refers to the general synthetic preparation of compoundsrepresented by Formula I. The preparation of compounds represented byFormula A, where R=lower alkyl, have been described previously. A fewexamples: Journal of Heterocyclic Chemistry 1968, 5(1), 35-39; IIFarmaco—Ed. Sci. 1977, 36(6), 430-437; Journal of Heterocyclic Chemistry2002, 39, 737-742. The direct installation of the R¹ substituent to givethe compound of Formula B can be accomplished by C—H insertion/directarylation reactions. These transformations can be carried out bytreatment with an appropriate aryl halide, a metal source (palladium(II)acetate, tetrakis(triphenylphosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0), copper iodide), a ligand(triphenylphosphine, bis(adamant-1-yl)(butyl)phosphine,1,10-phenanthroline) and a base (potassium carbonate, cesium carbonate,potassium tert-butoxide) in an appropriate solvent usually heated totemperatures above 50° C. (RSC Advances 2012, 2(14), 5972-5975; OrganicLetters 2012, 14(7), 1688-1691; PCT Int. Appl. 2011075643). During thisstep the (R³)_(b) and R¹ moieties should be represented by the samemoiety as is desired in the final product. For instance, in the compoundof Example 1, b is 0, and R¹ is a 4-chlorophenyl moiety. Theintermediate of Formula B can then be converted to compounds of FormulaI through treatment of the ester with the appropriate amine using heatand a Lewis acid, such as magnesium methoxide or calcium chloride, in anappropriate solvent (see Tetrahedron Letters 2010, 51, 3879-3882).During this step, the R⁶ and R⁷ moieties should be represented by thesame moiety as is desired in the final product. For instance, in Example4, R⁶ is cyclopropyl and R⁷ is hydrogen. Alternatively, the conversionof ester of Formula B to the amide of Formula I can be effected througha two-step process in which the ester is first hydrolyzed to the acid,via acidic or basic treatment in water and a co-solvent; the acid issubsequently converted to the amide by treatment with the appropriateamine in the presence of an amide coupling/dehydrating reagent such as2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), 1,3-dicyclohexylcarbodiimide (DCC), etc., attemperatures ranging from −20° C. to 100° C. to afford compounds ofFormula I. During either of these steps the R¹ moiety should berepresented by the same moiety as is desired in the final product. Forinstance, in Example 1, R¹ should be represented by a 4-chlorophenylmoiety.

Alternately, halogenation of the compound of Formula A by treatment withan electrophilic halogen reagent such as N-iodosuccinimide (NIS),N-bromosuccinimide (NBS), iodine monochloride (ICI), iodine (I₂),bromine (Br₂), etc., in an inert solvent, optionally acid-catalyzed,from room temperature to 100° C., results in the compound of Formula Cwherein X is represented by bromine or iodine. The compound of Formula Ccan be converted into a compound of Formula I in two ways. The firstmethod employs a substitution of the halogenated imidazopyridazine ofFormula C via a Suzuki-Miyaura reaction (Chemical Society Reviews 2014,43, 412-443; Accounts of Chemical Research 2013, 46, 2626-2634):treatment with an appropriate alkyl, aryl, or heteroaryl boronate in thepresence of base, a transition metal catalyst [potentially palladium(II)acetate or tris(dibenzylideneacetone)dipalladium(0)], and ametal-chelating ligand (generally phosphine-based), in an appropriatesolvent installs the appropriate R¹ moiety and affords Formula B. Thecompound of Formula B is then converted to the compound of Formula I asdescribed previously. In a second approach, the intermediate of FormulaC may be converted to amide D by treatment of the ester with theappropriate amine in the presence of heat and a Lewis acid, such asmagnesium methoxide or calcium chloride. Alternatively, transformationof the intermediate of Formula C to the compound of Formula D may becarried out in a two-step process in which the ester is hydrolyzed to anacid by treatment with basic or acidic water in a suitable co-solvent.The resulting acid is then converted to the compound of Formula D bytreatment with the appropriate amine in the presence of an amidecoupling/dehydrating reagent such as2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), 1,3-dicyclohexylcarbodiimide (DCC), etc., attemperatures ranging from −20° C. to 100° C. The intermediate of FormulaD can then be transformed into the compound of Formula I through aSuzuki-Miyaura reaction (Chemical Society Reviews 2014, 43, 412-443;Accounts of Chemical Research 2013, 46, 2626-2634): treatment with anappropriate alkyl, aryl, or heteroaryl boronate in the presence of base,a transition metal catalyst [potentially palladium(II) acetate ortris(dibenzylideneacetone)dipalladium(0)], and a metal-chelating ligand(generally phosphine-based), in an appropriate solvent, installs therequisite R¹ moiety.

Experimental Procedures

The following illustrate the synthesis of various compounds of thepresent invention. Additional compounds within the scope of thisinvention may be prepared using the methods illustrated in theseExamples, either alone or in combination with techniques generally knownin the art.

Experiments were generally carried out under inert atmosphere (nitrogenor argon), particularly in cases where oxygen- or moisture-sensitivereagents or intermediates were employed. Commercial solvents andreagents were generally used without further purification. Anhydroussolvents were employed where appropriate, generally AcroSeal® productsfrom Acros Organics or DriSolv® products from EMD Chemicals. In othercases, commercial solvents were passed through columns packed with 4 Åmolecular sieves, until the following QC standards for water wereattained: a) <100 ppm for dichloromethane, toluene,N,N-dimethylformamide and tetrahydrofuran; b) <180 ppm for methanol,ethanol, 1,4-dioxane and diisopropylamine. For very sensitive reactions,solvents were further treated with metallic sodium, calcium hydride ormolecular sieves, and distilled just prior to use. Products weregenerally dried under vacuum before being carried on to furtherreactions or submitted for biological testing. Mass spectrometry data isreported from either liquid chromatography-mass spectrometry (LCMS),atmospheric pressure chemical ionization (APCI) or gaschromatography-mass spectrometry (GCMS) instrumentation. Chemical shiftsfor nuclear magnetic resonance (NMR) data are expressed in parts permillion (ppm, δ) referenced to residual peaks from the deuteratedsolvents employed. In some examples, chiral separations were carried outto separate enantiomers of certain compounds of the invention (in someexamples, the separated enantiomers are designated as ENT-1 and ENT-2,according to their order of elution). In some examples, the opticalrotation of an enantiomer was measured using a polarimeter. According toits observed rotation data (or its specific rotation data), anenantiomer with a clockwise rotation was designated as the(+)-enantiomer and an enantiomer with a counter-clockwise rotation wasdesignated as the (−)-enantiomer.

Reactions proceeding through detectable intermediates were generallyfollowed by LCMS, and allowed to proceed to full conversion prior toaddition of subsequent reagents. For syntheses referencing procedures inother Examples or Methods, reaction conditions (reaction time andtemperature) may vary. In general, reactions were followed by thin-layerchromatography or mass spectrometry, and subjected to work-up whenappropriate. Purifications may vary between experiments: in general,solvents and the solvent ratios used for eluents/gradients were chosento provide appropriate R_(f)s or retention times.

Example 1Azetidin-1-yl[3-(4-chlorophenyl)imidazo[1,2-b]pyridazin-2-yl]methanone(1)

Step 1. Synthesis of ethyl imidazo[1,2-b]pyridazine-2-carboxylate (C1)

A mixture of pyridazin-3-amine (20 g, 210 mmol) and ethyl3-bromo-2-oxopropanoate (82 g, 420 mmol) in ethanol (300 mL) was heatedat reflux for 16 hours. After removal of solvent via distillation, theresidue was taken up in 2 M hydrochloric acid (100 mL) and washed withethyl acetate. The aqueous layer was basified to a pH of approximately 8via addition of aqueous sodium bicarbonate solution and then extractedwith chloroform; this organic layer was dried over sodium sulfate,filtered, and concentrated in vacuo. Silica gel chromatography (Eluent:20% ethyl acetate in petroleum ether) afforded the product as a brownsolid. Yield: 8.0 g, 42 mmol, 20%. LCMS m/z 192.0 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 8.53 (s, 1H), 8.39 (dd, J=4.4, 1.6 Hz, 1H), 8.01-8.04 (m,1H), 7.12 (dd, J=9.3, 4.4 Hz, 1H), 4.48 (q, J=7.1 Hz, 2H), 1.45 (t,J=7.1 Hz, 3H).

Step 2. Synthesis of ethyl 3-iodoimidazo[1,2-b]pyridazine-2-carboxylate(C2)

N-Iodosuccinimide (24.6 g, 109 mmol) was added to a solution of C1 (19g, 99 mmol) in acetonitrile (250 mL), and the reaction mixture wasstirred at room temperature for 24 hours. Additional N-iodosuccinimide(1 equivalent after every 24 hours) was introduced and stirringcontinued for a further 48 hours (72 hours overall), until completeconsumption of starting material was indicated via thin layerchromatographic analysis. After removal of solvent in vacuo, the residuewas taken up in dichloromethane and washed with 1 M hydrochloric acidand with water. The organic layer was dried over sodium sulfate,filtered, and concentrated under reduced pressure; silica gelchromatography (Eluent: 20% ethyl acetate in petroleum ether) providedthe product as an off-white solid. Yield: 14.5 g, 45.7 mmol, 46%. LCMSm/z 318.0 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 8.74 (dd, J=4.3, 1.3 Hz,1H), 8.18 (dd, J=9.2, 1.4 Hz, 1H), 7.41 (dd, J=9.3, 4.4 Hz, 1H), 4.35(q, J=7.0 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H).

Step 3. Synthesis of ethyl3-(4-chlorophenyl)imidazo[1,2-b]pyridazine-2-carboxylate (C3)

Aqueous sodium carbonate solution (3 M, 8.4 mL, 25 mmol) was added to amixture of C2 (2.00 g, 6.31 mmol), (4-chlorophenyl)boronic acid (1.48 g,9.46 mmol), and[1,1′-bis(dicyclohexylphosphino)ferrocene]dichloropalladium(II) (382 mg,0.505 mmol) in 1,4-dioxane (32 mL). The reaction mixture was heated at90° C. overnight, whereupon it was partitioned between ethyl acetate(150 mL) and water (50 mL). The aqueous layer was extracted with ethylacetate (3×150 mL), and the combined organic layers were dried overmagnesium sulfate, filtered, and concentrated in vacuo. Purification viasilica gel chromatography (Gradient: 0% to 100% ethyl acetate inheptane) afforded the product. Yield: 1.25 g, 4.14 mmol, 66%. LCMS m/z302.0, 304.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.39 (dd, J=4.3, 1.5 Hz,1H), 8.09 (dd, J=9.3, 1.5 Hz, 1H), 7.65 (br d, J=8.5 Hz, 2H), 7.50 (brd, J=8.5 Hz, 2H), 7.17 (dd, J=9.3, 4.3 Hz, 1H), 4.42 (q, J=7.1 Hz, 2H),1.38 (t, J=7.1 Hz, 3H).

Step 4. Synthesis of 3-(4-chlorophenyl)imidazo[1,2-b]pyridazine-2-carboxylic acid, sodium salt (C4)

A solution of C3 (1.75 g, 5.80 mmol) in methanol (25 mL) andtetrahydrofuran (25 mL) was added to an aqueous solution of sodiumhydroxide (2 M, 25 mL), and the reaction mixture was stirred at roomtemperature for 4 hours. The resulting solid was collected viafiltration and washed with cold water (2×25 mL) to provide the productas a solid. Yield: 1.50 g, 5.07 mmol, 87%. LCMS m/z 274.0, 276.0 [M+H]⁺.

Step 5. Synthesis ofazetidin-1-yl[3-(4-chlorophenyl)imidazo[1,2-b]pyridazin-2-yl]methanone(1)

Compound C4 (1.40 g, 4.74 mmol) was combined withO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU, 2.92 g, 7.70 mmol) and N,N-diisopropylethylamine (3.56 mL, 20.4mmol) in N,N-dimethylformamide (75 mL). After 2 minutes, azetidinehydrochloride (957 mg, 10.2 mmol) was added, and the reaction mixturewas stirred at 50° C. overnight. After removal of solvent in vacuo, theresidue was subjected to chromatography on silica gel (Gradient: 0% to100% ethyl acetate in heptane) followed by trituration with ethylacetate (30 mL) at 50° C.; this mixture was cooled to 0° C. andfiltered. The collected solid was washed with diethyl ether (50 mL) andwith cold ethyl acetate (15 mL). Subsequent recrystallization from ethylacetate provided the product as an off-white solid. Yield: 980 mg, 3.13mmol, 66%. LCMS m/z 313.2, 315.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.41(dd, J=4.4, 1.6 Hz, 1H), 8.10 (br d, J=9.2 Hz, 1H), 7.75 (br d, J=8.6Hz, 2H), 7.48 (br d, J=8.6 Hz, 2H), 7.19 (dd, J=9.2, 4.3 Hz, 1H),4.46-4.57 (m, 2H), 4.17-4.28 (m, 2H), 2.28-2.39 (m, 2H).

Example 23-(4-Chlorophenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide(2)

O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate(97%, 3.21 g, 8.21 mmol) was added to a mixture of the carboxylic acidof C4 (prepared in the same manner as C4, but in this case acidifiedwith hydrochloric acid, to afford the carboxylic acid rather than thesodium salt) (1.50 g, 5.48 mmol) and N,N-diisopropylethylamine (2.86 mL,16.4 mmol) in tetrahydrofuran (100 mL), and the reaction mixture wasstirred at room temperature for 2 minutes. Cyclopropylamine (0.77 mL, 11mmol) was introduced, and stirring was continued at room temperatureovernight. The reaction mixture was concentrated in vacuo and theresidue was subjected to silica gel chromatography (Gradient: 0% to 100%ethyl acetate in heptane). The resulting solid was triturated with a10:1 mixture of diethyl ether and dichloromethane, and subsequentlypurified once more via chromatography on silica gel (Gradient: 0% to100% ethyl acetate in heptane) to afford the product as a solid. Yield:1.39 g, 4.44 mmol, 81%. LCMS m/z 313.3, 315.2 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.46 (dd, J=4.3, 1.6 Hz, 1H), 8.06 (dd, J=9.3, 1.7 Hz, 1H),7.71 (br d, J=8.7 Hz, 2H), 7.48 (br d, J=8.6 Hz, 2H), 7.31 (dd, J=9.3,4.4 Hz, 1H), 2.79-2.86 (m, 1H), 0.78-0.84 (m, 2H), 0.62-0.68 (m, 2H).

Example 3Azetidin-1-yl[3-(3,5-difluoro-4-methoxyphenyl)imidazo[1,2-b]pyridazin-2-yl]methanone(3)

Step 1. Synthesis of ethyl3-(3,5-difluoro-4-methoxyphenyl)imidazo[1,2-b]pyridazine-2-carboxylate(C5)

A mixture of C1 (500 mg, 2.6 mmol),5-bromo-1,3-difluoro-2-methoxybenzene (864 mg, 3.87 mmol), and potassiumcarbonate (866 mg, 6.27 mmol) in N,N-dimethylformamide (10 mL) wasdegassed with nitrogen several times. Palladium(II) acetate (50 mg, 0.22mmol) and tetrakis(triphenylphosphine)palladium(0) (30 mg, 26 μmol) wereadded, and the reaction mixture was stirred at 110° C. overnight. Afteraddition of water (50 mL), the mixture was extracted with ethyl acetate(3×30 mL); the combined organic layers were concentrated in vacuo andpurified by chromatography on silica gel to provide the product as ayellow solid. Yield: 500 mg, 1.5 mmol, 58%. LCMS m/z 334.0 [M+H]⁺.

Step 2. Synthesis of 3-(3, 5-difluoro-4-methoxyphenyl)imidazo[1,2-b]pyridazine-2-carboxylic acid (C6)

To a solution of C5 (500 mg, 1.5 mmol) in ethanol (30 mL) was added asolution of lithium hydroxide (2 equivalents) in water (10 mL), and thereaction mixture was stirred at room temperature for 4 hours, whereuponit was concentrated in vacuo. The residue was diluted with water andacidified to a pH of 4 with hydrochloric acid. After extraction of themixture with dichloromethane (3×30 mL), the combined organic layers wereconcentrated under reduced pressure to afford the product as a yellowsolid, which was used in the next step without additional purification.Yield: 500 mg, quantitative. LCMS m/z 305.9 [M+H]⁺.

Step 3. Synthesis ofazetidin-1-yl[3-(3,5-difluoro-4-methoxyphenyl)imidazo[1,2-b]pyridazin-2-yl]methanone(3)

A mixture of C6 (100 mg, 0.328 mmol), azetidine hydrochloride (45 mg,0.48 mmol), 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 186 mg, 0.489 mmol),N,N-diisopropylethylamine (126 mg, 0.975 mmol) and N,N-dimethylformamide(10 mL) was stirred at room temperature overnight. The reaction mixturewas then diluted with water and extracted with ethyl acetate (3×10 mL).The combined organic layers were concentrated in vacuo and purified byreversed phase HPLC (Column: Phenomenex Synergi C18, 4 μm; Mobile phaseA: 0.225% formic acid in water; Mobile phase B: acetonitrile; Gradient:33% to 53% B) to provide the product as a yellow solid. Yield: 35.7 mg,0.104 mmol, 32%. LCMS m/z 344.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.63(dd, J=4.4, 1.6 Hz, 1H), 8.24 (dd, J=9.3, 1.6 Hz, 1H), 7.56 (br d, J=9.9Hz, 2H), 7.39 (dd, J=9.4, 4.4 Hz, 1H), 4.46-4.53 (m, 2H), 4.01-4.07 (m,2H), 4.01 (br s, 3H), 2.22-2.32 (m, 2H).

Example 4N-Cyclopropyl-3-(2-methoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carboxamide(4)

Step 1. Synthesis of ethyl3-(2-methoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carboxylate (C7)

A mixture of C2 (1.8 g, 5.7 mmol), (2-methoxypyrimidin-5-yl)boronic acid(1.3 g, 8.4 mmol), sodium carbonate (1.8 g, 17 mmol) and 1,4-dioxane (30mL) was degassed several times with nitrogen.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 mg, 40μmol) was added, and the reaction mixture was stirred at 110° C.overnight. It was then diluted with water and extracted with ethylacetate (4×100 mL); the combined organic layers were washed withsaturated aqueous sodium chloride solution, dried over sodium sulfate,filtered, and concentrated under reduced pressure. Purification viachromatography on silica gel provided the product as a yellow solid.Yield: 800 mg, 2.7 mmol, 47%. LCMS m/z 299.7 [M+H]⁺.

Step 2. Synthesis ofN-cyclopropyl-3-(2-methoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carboxamide(4)

Cyclopropylamine (5 mL, 70 mmol) was added to a mixture of C7 (800 mg,2.7 mmol) and calcium chloride (200 mg, 1.8 mmol) in methanol (200 mL).The reaction mixture was stirred at 50° C. for 5 hours, whereupon it wasdiluted with water and extracted with ethyl acetate (2×100 mL). Thecombined organic layers were washed with saturated aqueous sodiumchloride solution, dried over sodium sulfate, filtered, and concentratedin vacuo. Purification via reversed phase HPLC (Column: Agella VenusilASB C18, 5 μm; Mobile phase A: 0.225% formic acid in water; Mobile phaseB: acetonitrile; Gradient: 29% to 49% B) afforded the product as a whitesolid. Yield: 430.3 mg, 1.39 mmol, 51%. LCMS m/z 311.0 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃) δ 9.01 (s, 2H), 8.40 (dd, J=4.4, 1.6 Hz, 1H), 7.97 (dd,J=9.2, 1.7 Hz, 1H), 7.60 (br s, 1H), 7.20 (dd, J=9.3, 4.3 Hz, 1H), 4.10(s, 3H), 2.88-2.95 (m, 1H), 0.84-0.91 (m, 2H), 0.66-0.72 (m, 2H).

Example 53-(6-Cyanopyridin-3-yl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide(5)

Step 1. Synthesis of ethyl 3-bromoimidazo[1,2-b]pyridazine-2-carboxylate(C8)

N-Bromosuccinimide (25.6 g, 144 mmol) was added to a 0° C. solution ofC1 (25.0 g, 131 mmol) in dichloromethane (250 mL). The reaction mixturewas allowed to gradually warm to room temperature and stir overnight,whereupon the reaction was quenched with 10% aqueous sodium bisulfitesolution. The resulting mixture was diluted with additionaldichloromethane and washed with saturated aqueous sodium bicarbonatesolution and with water. The organic layer was dried over magnesiumsulfate, filtered, and concentrated in vacuo. Trituration withtert-butyl methyl ether afforded the product as a pinkish-mauve solid(25.4 g). Concentration of the filtrate under reduced pressure wasfollowed by trituration with tert-butyl methyl ether and hexanes to givea second batch of product (6.46 g). Combined yield: 31.9 g, 118 mmol,90%. LCMS m/z 270.0, 272.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.55 (dd,J=4.4, 1.6 Hz, 1H), 8.05 (dd, J=9.3, 1.6 Hz, 1H), 7.22 (dd, J=9.3, 4.4Hz, 1H), 4.53 (q, J=7.1 Hz, 2H), 1.49 (t, J=7.1 Hz, 3H).

Step 2. Synthesis of3-bromo-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide (C9)

A mixture of C8 (27.0 g, 100 mmol), cyclopropylamine (25.0 mL, 349mmol), and calcium chloride (12.2 g, 110 mmol) in methanol (250 mL) washeated at 50° C. for 3 days, whereupon it was cooled to room temperatureand concentrated in vacuo. The residue was partitioned betweendichloromethane and water, and the organic layer was concentrated underreduced pressure. Trituration of the residue with diethyl ether andwater afforded the product as a pink solid. Yield: 24.4 g, 86.8 mmol,87%. LCMS m/z 281.0, 283.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.52 (dd,J=4.4, 1.6 Hz, 1H), 7.90 (dd, J=9.3, 1.6 Hz, 1H), 7.46 (br s, 1H), 7.20(dd, J=9.2, 4.4 Hz, 1H), 2.91-2.98 (m, 1H), 0.86-0.92 (m, 2H), 0.67-0.72(m, 2H).

Step 3. Synthesis of3-(6-cyanopyridin-3-yl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide(5)

To a degassed solution of C9 (300 mg, 1.07 mmol) in2-methyltetrahydrofuran (7 mL) and water (2 mL) was added potassiumphosphate (80%, 849 mg, 3.20 mmol). The mixture was heated to 80° C.,and then treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),dichloromethane complex (97%, 53.9 mg, 64.0 μmol). After 2 minutes,5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile(319 mg, 1.39 mmol) was added, and the reaction mixture was maintainedat 80° C. overnight. It was then allowed to cool to room temperature andwas filtered through diatomaceous earth; the filter pad was rinsed withethyl acetate, and the combined filtrates were washed with water. Afterthe organic layer had been concentrated in vacuo, the residue waspurified via silica gel chromatography (Gradient: 50% to 100% ethylacetate in heptane) to afford a white solid (196 mg). Recrystallizationfrom methanol afforded the product as colorless needles. Yield: 135 mg,0.444 mmol, 41%. LCMS m/z 305.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.18(d, J=1.5 Hz, 1H), 8.41-8.46 (m, 2H), 8.01 (dd, J=9.2, 1.4 Hz, 1H), 7.82(d, J=8.0 Hz, 1H), 7.66 (br s, 1H), 7.26 (dd, J=9.2, 4.4 Hz, 1H),2.86-2.94 (m, 1H), 0.85-0.92 (m, 2H), 0.66-0.72 (m, 2H).

Example 6N-Cyclopropyl-3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazo[1,2-b]pyridazine-2-carboxamide(6)

Compound C9 (1.90 g, 6.76 mmol) was combined with6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)[1,2,4]triazolo[1,5-a]pyridine(1.82 g, 7.43 mmol),[1,1′-bis(dicyclohexylphosphino)ferrocene]dichloropalladium(II) (51.4mg, 68.0 μmol), and 1,4-dioxane (34 mL). Aqueous sodium carbonatesolution (3 M, 9.0 mL, 27 mmol) was added, and the reaction mixture waspurged with nitrogen for 15 minutes, then heated at 100° C. for 20hours. The reaction mixture was cooled to room temperature and thesupernatant was immediately filtered through a pad of diatomaceousearth, rinsing with 10% methanol in ethyl acetate. Remaining solids werepartitioned between half-saturated aqueous sodium chloride solution (25mL) and 10% methanol in ethyl acetate by stirring for 5 minutes; thismixture was also filtered through diatomaceous earth. The combinedfiltrates were diluted with saturated aqueous sodium chloride solution(25 mL) and additional 10% methanol in ethyl acetate. The aqueous layerwas extracted three times with 10% methanol in ethyl acetate, and thecombined organic layers were washed with saturated aqueous sodiumchloride solution, dried over sodium sulfate, filtered, and concentratedin vacuo. The residue was adsorbed onto diatomaceous earth (4-fold theweight of the crude product) using dichloromethane and methanol, andsubjected to chromatography on silica gel (Gradient: 0% to 20% methanolin ethyl acetate). The resulting material (1.83 g) was mixed withmethanol (20 mL) and heated to 72° C. for 20 minutes; after cooling, themixture was filtered and washed with methanol to afford the product asan off-white solid. This material was found to be crystalline via powderX-ray diffraction. Yield: 1.66 g, 5.20 mmol, 77%. LCMS m/z 320.2 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 9.35 (dd, J=1.4, 1.3 Hz, 1H), 8.64 (dd,J=4.4, 1.6 Hz, 1H), 8.61 (br d, J=5 Hz, 1H), 8.60 (s, 1H), 8.24 (dd,J=9.3, 1.6 Hz, 1H), 7.93-7.99 (m, 2H), 7.44 (dd, J=9.3, 4.4 Hz, 1H),2.82-2.90 (m, 1H), 0.64-0.70 (m, 4H).

Example 73-(4-Chloro-3-fluorophenyl)-N-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide(7)

Step 1. Synthesis of ethyl3-(4-chloro-3-fluorophenyl)imidazo[1,2-b]pyridazine-2-carboxylate (C10)

Aqueous sodium carbonate solution (3 M, 8.8 mL, 26 mmol) was added to amixture of C2 (2.10 g, 6.62 mmol), (4-chloro-3-fluorophenyl)boronic acid(1.73 g, 9.92 mmol), and[1,1′-bis(dicyclohexylphosphino)ferrocene]dichloropalladium(II) (401 mg,0.530 mmol) in 1,4-dioxane (34 mL), and the reaction mixture was heatedat 85° C. overnight. It was then diluted with water (75 mL) andextracted with ethyl acetate (4×250 mL). The combined organic layerswere dried over magnesium sulfate, filtered, and concentrated in vacuo;purification via chromatography on silica gel (Gradient: 5% to 100%ethyl acetate in heptane) afforded the product. Yield: 1.50 g, 4.69mmol, 71%. LCMS m/z 320.0, 322.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.43(br d, J=4.3 Hz, 1H), 8.11 (br d, J=9.3 Hz, 1H), 7.52-7.58 (m, 2H),7.46-7.50 (m, 1H), 7.22 (dd, J=9.3, 4.4 Hz, 1H), 4.44 (q, J=7.1 Hz, 2H),1.39 (t, J=7.1 Hz, 3H).

Step 2. Synthesis of 3-(4-chloro-3-fluorophenyl)imidazo[1,2-b]pyridazine-2-carboxylic acid, lithium salt (C11)

A mixture of C10 (700 mg, 2.2 mmol) and lithium hydroxide monohydrate(200 mg, 4.8 mmol) in methanol (100 mL) and water (30 mL) was stirred atroom temperature for 16 hours. The reaction mixture was concentrated toremove methanol, and the residue was washed with ethyl acetate.Collection of the resulting solid via filtration afforded the product asa yellow solid. Yield: 700 mg, quantitative. ¹H NMR (400 MHz, DMSO-d₆) δ8.56 (br d, J=4 Hz, 1H), 8.13 (br d, J=9 Hz, 1H), 7.97 (d, J=11 Hz, 1H),7.79 (d, J=8 Hz, 1H), 7.65 (dd, J=8.5, 8 Hz, 1H), 7.32 (dd, J=9.3, 4.3Hz, 1H).

Step 3. Synthesis of3-(4-chloro-3-fluorophenyl)-N-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide(7)

A mixture of C11 (200 mg, 0.67 mmol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (500 mg, 1.3 mmol) in N,N-dimethylformamide (5 mL)and N,N-diisopropylethylamine (2 mL) was stirred at room temperature for20 minutes. 1-Methyl-1H-pyrazol-4-amine (200 mg, 2.1 mmol) was added,and the reaction mixture was stirred at 35° C. for 2 hours, whereupon itwas diluted with water and filtered. The collected solid was washed withethyl acetate and methanol to provide the product as a pink solid.Yield: 130 mg, 0.351 mmol, 52%. LCMS m/z 393.0 [M+Na⁺]. ¹H NMR (400 MHz,DMSO-d₆) δ 10.76 (s, 1H), 8.64 (br d, J=4.4 Hz, 1H), 8.26 (br d, J=9.4Hz, 1H), 8.04 (s, 1H), 7.82 (br d, J=10.7 Hz, 1H), 7.73 (dd, J=8.3, 8.0Hz, 1H), 7.66 (s, 1H), 7.61 (br d, J=8.4 Hz, 1H), 7.44 (dd, J=9.3, 4.3Hz, 1H), 3.79 (s, 3H).

Example 8Azetidin-1-yl[3-(pyrazolo[1,5-a]pyridin-6-yl)imidazo[1,2-b]pyridazin-2-yl]methanone(8)

Step 1. Synthesis of6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine(C12)

A mixture of 6-bromopyrazolo[1,5-a]pyridine (1.5 g, 7.6 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (2.03 g, 7.99mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.27g, 0.37 mmol), and potassium acetate (2.2 g, 22 mmol) in 1,4-dioxane (25mL) was degassed for 10 minutes, and then heated at 100° C. overnight.After removal of solvent in vacuo, the residue was diluted withdichloromethane, mixed with diatomaceous earth (˜5 g), and concentratedunder reduced pressure. Silica gel chromatography (Gradient: 0% to 50%ethyl acetate in heptane) afforded the product as a green liquid. Yield:1.35 g, 5.53 mmol, 73%. GCMS m/z 244 [M⁺]. ¹H NMR (400 MHz, CDCl₃) δ8.86-8.87 (m, 1H), 7.99 (d, J=2.2 Hz, 1H), 7.50 (dd, J=8.8, 1.1 Hz, 1H),7.37 (dd, J=8.8, 1.1 Hz, 1H), 6.49 (dd, J=2.2, 0.9 Hz, 1H), 1.37 (s,12H).

Step 2. Synthesis ofazetidin-1-yl(3-bromoimidazo[1,2-b]pyridazin-2-yl)methanone (C13)

A mixture of azetidine hydrochloride (1.73 g, 18.5 mmol) andtriethylamine (2.57 mL, 18.5 mmol) in anhydrous methanol (18 mL) wasstirred at room temperature for 10 minutes. Compound C8 (500 mg, 1.85mmol) and calcium chloride (206 mg, 1.86 mmol) were added, the reactionvessel was tightly capped, and the reaction mixture was heated at 50° C.overnight. After removal of solvent in vacuo, the residue waspartitioned between water (25 mL) and dichloromethane (100 mL). Theorganic layer was dried over magnesium sulfate, filtered, andconcentrated under reduced pressure; chromatography on silica gel(Eluent: ethyl acetate) afforded the product as a light yellow solid.Yield: 357 mg, 1.27 mmol, 69%. LCMS m/z 281.0, 283.0 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 8.45 (dd, J=4.4, 1.6 Hz, 1H), 7.87 (dd, J=9.2, 1.6 Hz,1H), 7.12 (dd, J=9.2, 4.4 Hz, 1H), 4.59-4.65 (m, 2H), 4.17-4.24 (m, 2H),2.27-2.37 (m, 2H).

Step 3. Synthesis ofazetidin-1-yl[3-(pyrazolo[1,5-a]pyridin-6-yl)imidazo[1,2-b]pyridazin-2-yl]methanone(8)

A flask containing a solution of C13 (1.06 g, 3.77 mmol) in toluene (60mL) was evacuated under high vacuum and then filled with nitrogen.Repeating the evacuation/nitrogen fill after each addition, C12 (2.84 g,11.6 mmol) was added, followed by a solution of cesium fluoride (2.87 g,18.9 mmol) in water (18 mL), and a solution ofbis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II)(335 mg, 0.473 mmol) in 1,2-dichloroethane (9 mL). The reaction mixturewas heated at 100° C. for 23 hours, whereupon it was cooled to roomtemperature, concentrated in vacuo, and subjected to chromatography onsilica gel (Eluents: ethyl acetate, then 5% methanol indichloromethane). This material was combined with the product from asimilar reaction carried out on C13 (200 mg, 0.71 mmol) and purified viasupercritical fluid chromatography (Column: PrincetonMethanesulfonamide, 5 μm; Mobile phase: 4:1 carbon dioxide/methanol).The resulting material was recrystallized from ethanol to afford theproduct as a white solid. This material was found to be crystalline viapowder X-ray diffraction. Yield: 540 mg, 1.7 mmol, 38%. LCMS m/z 319.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.07 (br s, 1H), 8.40 (dd, J=4.3, 1.6Hz, 1H), 8.01 (d, J=2.2 Hz, 1H), 8.01 (dd, J=9.3, 1.7 Hz, 1H), 7.63 (d,half of AB quartet, J=9.3 Hz, 1H), 7.54 (dd, half of ABX pattern, J=9.2,1.4 Hz, 1H), 7.16 (dd, J=9.3, 4.4 Hz, 1H), 6.56 (d, J=2.2 Hz, 1H),4.59-4.65 (m, 2H), 4.20-4.27 (m, 2H), 2.31-2.40 (m, 2H).

Example 93-(4-Chloro-2,5-difluorophenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide(9)

Potassium phosphate (80%, 1.42 g, 5.35 mmol) was added to a degassedsolution of C9 (500 mg, 1.78 mmol) in 2-methyltetrahydrofuran (20 mL)and water (5 mL), and the mixture was heated to 80° C.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II),dichloromethane complex (97%, 90.1 mg, 0.107 mmol) was introduced, andafter 2 minutes,2-(4-chloro-2,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(635 mg, 2.31 mmol) was added. The reaction mixture was maintained at80° C. overnight, whereupon it was cooled to room temperature andfiltered through diatomaceous earth. The filter pad was rinsed withethyl acetate, and the combined filtrates were washed with water; theorganic layer was concentrated in vacuo and purified via silica gelchromatography (Gradient: 50% to 100% ethyl acetate in heptane).Recrystallization from methanol afforded the product as an off-whitesolid. Yield: 217 mg, 0.622 mmol, 35%. LCMS m/z 349.1, 351.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.40 (dd, J=4.4, 1.7 Hz, 1H), 7.98 (dd, J=9.3,1.6 Hz, 1H), 7.53 (br s, 1H), 7.50 (dd, J=8.9, 5.9 Hz, 1H), 7.31 (dd,J=8.6, 6.1 Hz, 1H), 7.21 (dd, J=9.3, 4.4 Hz, 1H), 2.86-2.93 (m, 1H),0.84-0.89 (m, 2H), 0.66-0.71 (m, 2H).

Using the methodology described above for Examples 1-9, Examples 10-25were synthesized. See Table 1 for specific methods employed, as well ascharacterization data for these Examples.

TABLE 1 Method of preparation, structure, and physicochemical data forExamples 10-25. Method of Synthesis: Example ¹H NMR (400 MHz, CDCl₃)Number; δ (ppm); Mass spectrum, Source of observed ion m/z [M + H] orNon- HPLC retention time; Mass commercial spectrum m/z [M + H] ExampleStarting (unless otherwise Number Materials Structure indicated) 10Example 1; C11

¹H NMR (400 MHz, CD₃OD) δ 8.48 (dd, J = 4.3, 1.4 Hz, 1H), 8.07 (dd, J =9.3, 1.4 Hz, 1H), 7.64- 7.69 (m, 1H), 7.53-7.59 (m, 2H), 7.33 (dd, J =9.3, 4.4 Hz, 1H), 2.79-2.87 (m, 1H), 0.78-0.85 (m, 2H), 0.63- 0.69 (m,2H); 331.1, 333.1 11 Example 4¹; C8

8.40 (dd, J = 4.4, 1.6 Hz, 1H), 7.96 (dd, J = 9.3, 1.6 Hz, 1H), 7.93 (d,J = 1.9 Hz, 1H), 7.70 (dd, half of ABX pattern, J = 8.3, 2.1 Hz, 1H),7.60 (br s, 1H), 7.58 (d, half of AB quartet, J = 8.4 Hz, 1H), 7.19 (dd,J = 9.3, 4.4 Hz, 1H), 2.86-2.94 (m, 1H), 0.83-0.90 (m, 2H), 0.64- 0.71(m, 2H); 346.9 12 Example 5; C9

¹H NMR (400 MHz, DMSO- d₆) δ 8.54 (dd, J = 4.4, 1.6 Hz, 1H), 8.48 (br d,J = 4.9 Hz, 1H), 8.19 (dd, J = 9.3, 1.6 Hz, 1H), 7.45-7.47 (m, 1H), 7.37(dd, J = 9.3, 4.4 Hz, 1H), 7.33-7.35 (m, 2H), 2.76-2.84 (m, 1H), 1.99-2.00 (m, 3H), 0.62-0.65 (m, 4H); 327.1, 329.1 13 Example 7; C11

¹H NMR (400 MHz, DMSO- d₆) δ 8.62 (dd, J = 4.3, 1.5 Hz, 1H), 8.25 (dd, J= 9.3, 1.5 Hz, 1H), 7.81 (dd, J = 10.8, 1.9 Hz, 1H), 7.71 (dd, J = 8.3,8.0 Hz, 1H), 7.59 (br dd, J = 8.3, 1.4 Hz, 1H), 7.39 (dd, J = 9.3, 4.4Hz, 1H), 4.47-4.53 (m, 2H), 4.00-4.07 (m, 2H), 2.21- 2.32 (m, 2H); 330.814 Example 4²; C1

¹H NMR (400 MHz, DMSO- d₆) δ 8.85 (d, J = 1.6 Hz, 1H), 8.70 (d, J = 2.4Hz, 1H), 8.64 (dd, J = 4.4, 1.5 Hz, 1H), 8.62 (br d, J = 4.6 Hz, 1H),8.30 (dd, J = 2.1, 2.0 Hz, 1H), 8.23 (dd, J = 9.3, 1.5 Hz, 1H), 7.44(dd, J = 9.3, 4.4 Hz, 1H), 2.81- 2.90 (m, 1H), 0.63-0.70 (m, 4H), 313.915 Example 3; C1

¹H NMR (400 MHz, DMSO- d₆) δ 8.83 (d, J = 1.9 Hz, 1H), 8.68 (d, J = 2.4Hz, 1H), 8.64 (dd, J = 4.4, 1.5 Hz, 1H), 8.30 (dd, J = 2.4, 1.9 Hz, 1H),8.28 (dd, J = 9.3, 1.5 Hz, 1H), 7.42 (dd, J = 9.3, 4.4 Hz, 1H), 4.57-4.62 (m, 2H), 4.02-4.08 (m, 2H), 2.24-2.33 (m, 2H); 313.9 16 C1³

9.22 (br s, 1H), 8.40-8.44 (m, 2H), 7.98-8.07 (m, 2H), 7.86 (br d, J = 9Hz, 1H), 7.21 (dd, J = 9.4, 4.3 Hz, 1H), 4.68-4.75 (m, 2H), 4.21-4.28(m, 2H), 2.34- 2.44 (m, 2H); 319.8 17 Example 4⁴; C1

2.55 minutes⁵; 336.2 18 Example 4⁴; C1

2.46 minutes⁵; 336.2 19 Example 2⁶; C1

2.52 minutes⁵; 336.1 20 Example 8⁷; C13

¹H NMR (400 MHz, CD₃OD) δ 8.48 (dd, J = 4.3, 1.4 Hz, 1H), 8.14 (dd, J =9.3, 1.4 Hz, 1H), 7.74 (d, J = 6.5 Hz, 1H), 7.39 (d, J = 9.7 Hz, 1H),7.35 (dd, J = 9.3, 4.5 Hz, 1H), 4.73- 4.80 (m, 2H), 4.12-4.20 (m, 2H),2.36-2.45 (m, 2H), 2.08 (s, 3H); 335.9 21 Example 7; C11

¹H NMR (400 MHz, DMSO- d₆), characteristic peaks: δ 8.68 (br d, J = 4.4Hz, 1H), 8.27 (br d, J = 9 Hz, 1H), 7.87 (br d, J = 11 Hz, 1H), 7.76(dd, J = 8.3, 8.2 Hz, 1H), 7.57 (br d, J = 9 Hz, 1H), 7.42 (dd, J = 9.3,4.4 Hz, 1H), 2.99 and 2.80 (2 br s, total 3H), [0.31-0.42, 0.63-0.70 and0.75-0.83 (3 m, total 4H)]⁸; 345.1 22 Example 8; C9, C12

¹H NMR (400 MHz, CD₃OD) δ 9.01 (br s, 1H), 8.53 (dd, J = 4.2, 1.6 Hz,1H), 8.12 (dd, J = 9.3, 1.6 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.74 (brd, J = 9.0 Hz, 1H), 7.54 (dd, J = 9.2, 1.4 Hz, 1H), 7.36 (dd, J = 9.2,4.4 Hz, 1H), 6.67-6.70 (m, 1H), 2.81-2.88 (m, 1H), 0.79-0.86 (m, 2H),0.65- 0.71 (m, 2H); 341.0 [M + Na⁺] 23 Example 6¹; C13

8.42 (dd, J = 4.3, 1.6 Hz, 1H), 8.03 (dd, J = 9.3, 1.6 Hz, 1H),7.78-7.84 (m, 2H), 7.72 (dd, J = 8.4, 6.3 Hz, 1H), 7.21 (dd, J = 9.2,4.3 Hz, 1H), 4.60-4.66 (m, 2H), 4.21-4.27 (m, 2H), 2.33- 2.42 (m, 2H);322.2 24 Example 5; C13

8.41 (dd, J = 4.3, 1.6 Hz, 1H), 8.04 (dd, J = 9.3, 1.6 Hz, 1H), 7.64(dd, J = 8.8, 5.3 Hz, 1H), 7.45 (dd, J = 8.2, 5.0 Hz, 1H), 7.22 (dd, J =9.3, 4.4 Hz, 1H), 4.73-4.80 (m, 2H), 4.20- 4.26 (m, 2H), 2.36-2.45 (m,2H); 339.9 25 Example 5⁹; C8

2.64 minutes¹⁰; 3191. In this case, the catalyst used for the Suzuki reaction wasdichlorobis(tricyclohexylphosphine)palladium(II).2. The requisite ethyl3-(5-chloropyridin-3-yl)imidazo[1,2-b]pyridazine-2-carboxylate wassynthesized from C1 and 3-bromo-5-chloropyridine, using the methoddescribed for conversion of C1 to C5 in Example 3.3. Compound C1 was converted toazetidin-1-yl(imidazo[1,2-b]pyridazin-2-yl)methanone using the methoddescribed for transformation of C8 to C13 in Example 8. Furtherelaboration to Example 16 was effected using the chemistry described forconversion of C1 to C5 in Example 3.4. Reaction of C1 with 4-bromo-5-fluoro-2-methylbenzonitrile at elevatedtemperature, in the presence of allylpalladium chloride dimer andtetrabutylammonium acetate, afforded the requisite ethyl3-(4-cyano-2-fluoro-5-methylphenyl)imidazo[1,2-b]pyridazine-2-carboxylate.5. Conditions for analytical HPLC. Column: Waters Atlantis dC18, 4.6×50mm, 5 μm; Mobile phase A: 0.05% trifluoroacetic acid in water (v/v);Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v);Gradient: 5.0% to 95% B, linear over 4.0 minutes; Flow rate: 2mL/minute.6.3-(4-Cyano-5-fluoro-2-methylphenyl)imidazo[1,2-b]pyridazine-2-carboxylicacid was prepared from C1 and 4-bromo-2-fluoro-5-methylbenzonitrileusing the chemistry described in footnote 4, followed by esterhydrolysis with lithium hydroxide.7. The requisite aryl boronate derivative was prepared from thecorresponding aryl bromide via reaction with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane in thepresence of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)and potassium acetate.8. A ¹H NMR spectrum obtained at elevated temperature (80° C.) providedthe following data: ¹H NMR (400 MHz, DMSO-d₆), characteristic peaks: δ8.66 (br d, J=4 Hz, 1H), 8.23 (br d, J=9 Hz, 1H), 7.85 (br d, J=11 Hz,1H), 7.73 (dd, J=8, 8 Hz, 1H), 7.62 (br d, J=8 Hz, 1H), 7.40 (dd, J=9, 4Hz, 1H), 2.88-3.02 (br s, 3H), 0.28-0.61 (br s, 4H).9. In this case, the catalyst used for the Suzuki reaction was[1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II).10. Conditions for analytical HPLC. Column: Waters XBridge C18, 2.1×50mm, 5 μm; Mobile phase A: 0.0375% trifluoroacetic acid in water; Mobilephase B: 0.01875% trifluoroacetic acid in acetonitrile; Gradient: 1% to5% B over 0.6 minutes; 5% to 100% B over 3.4 minutes; Flow rate: 0.8mL/minute.

TABLE 2 Examples 26-104 were prepared using methods analogous to thoseemployed for Examples 1-25, or via methodology known to those skilled inthe art. Structure and mass spectrometry data for Examples 26-104. Massspectrum, observed ion m/z [M + H]⁺, unless Example otherwise NumberStructure indicated 26

314.9  27

326.9  28

348.8  29

354.9  [M + Na⁺] 30

326.9  31

343.1, 345.1  32

326.9  33

327.0  34

333.0  35

330.9  36

312.9  37

339.1  38

320.1  39

320.1  40

331.0, 333.1  41

311.1  42

347.9  43

347.9  44

367.0  45

349.1  46

353.0  [M + Na⁺] 47

348.9  48

315.9  49

327.1, 329.1  50

321.1  51

327.1, 329.0  52

330.9  53

325.1  54

310.9  55

326.9  56

327.2  57

393    58

354    59

354    60

331.1, 333.1  61

349.0, 351.0  62

331    63

339    64

327    65

347    66

341    67

337    68

348.9  69

331.9  70

344.8  71

344.8  72

328.9  73

326.9  74

319.8  75

346.1  76

346.0  77

320.1  78

320.1  79

343.9  [M + Na⁺] 80

318.2  81

319.0  82

357.1  83

346.9  84

312.9  85

300.8  86

359.1  87

346.1  88

320.1  89

333.9  90

322.2  91

349.2  92

340.1  93

323    94

305    95

315    96

337    97

347    98

324    99

338.1  100

351    101

350.9  102

348.9  [M + Na⁺] 103

339.0  104

348.9 

The PDE4A, PDE4B, PDE4C and PDE4D binding affinity for the compounds ofthe present invention was determined utilizing the following biologicalassay(s):

Biological Assays

Human PDE4A3 coding sequence (amino acids 2 to 825 from the sequencewith accession number NP_001104779) was cloned into the baculovirusexpression vector pFastBac (Invitrogen) engineered to include anN-terminal His6 affinity tag and a c-terminal FLAG affinity tag to aidin purification. The recombinant Bacmid was isolated and used totransfect insect cells to generate a viral stock. To generate cell pastefor purification, insect cells were infected with the virus stock andcells were harvested 72 hours after infection. Insect cell paste waslysed and after centrifugation, the supernatant was batch bound toNi-NTA agarose (GE Healthcare) and eluted with 250 mM imidazole. Thiseluate was diluted with FLAG buffer (50 mM Tris HCL pH 7.5, 100 mM NaCl,5% Glycerol, 1 mM TCEP with protease inhibitors) and batch bound toant-FLAG M2 agarose (Sigma) overnight at 4° C. The agarose was packedinto a column, washed with buffer and eluted with buffer containingelute using 250 ug/ml Flag-peptide. Fractions were analyzed usingSDS-PAGE Coomassie blue staining and pooled based on purity. Pooledfractions were chromatographed on a S200 120 ml column (GE Healthcare)in 50 mM Tris HCL pH 7.5, 150 mM NaCl, 10% Glycerol, 2 mM TCEP withprotease inhibitors. PDE4A3 fractions were analyzed by SDS-PAGECoomassie blue staining, pooled based on purity, dialyzed against 50 mMTris HCL pH 7.5, 100 mM NaCl, 20% Glycerol, 2 mM TCEP, frozen and storedat −80° C.

Human PDE4B1 coding sequence (amino acids 122 to 736 from the sequencewith accession number Q07343) with the mutations resulting in the aminoacid substitutions S134E, S654A, S659A, and S661A was cloned into thebaculovirus expression vector pFastBac (Invitrogen) engineered toinclude a N-terminal His6 affinity tag to aid in purification followedby a thrombin cleavage site. The recombinant Bacmid was isolated andused to transfect insect cells to generate a viral stock. To generatecell paste for purification, insect cells were infected with the virusstock and cells were harvested 72 hours after infection as described inSeeger, T. F. et al., Brain Research 985 (2003) 113-126. Insect cellpaste was lysed and after centrifugation, the supernatant waschromatographed on Ni-NTA agarose (Qiagen) as described in Seeger, T. F.et al., Brain Research 985 (2003) 113-126. Ni-NTA agarose elutingfractions containing PDE4 were pooled, diluted with Q buffer A (20 mMTris HCl pH 8, 5% glycerol, 1 mM TCEP) to reduce NaCl to ˜100 mM andloaded on a Source 15Q (GE Healthcare) column. After washing with Qbuffer A/10% buffer B to baseline, PDE4D was eluted with a gradient from10% to 60% of Buffer B (20 mM Tris HCl pH 8, 1 M NaCl, 5% glycerol, 1 mMTCEP). PDE4D fractions were analyzed by SDS-PAGE Coomassie bluestaining, pooled based on purity, frozen and stored at −80° C.

Human PDE4C1 coding sequence (amino acids 2 to 712 from the sequencewith accession number NP_000914.2) was cloned into the baculovirusexpression vector pFastBac (Invitrogen) engineered to include anN-terminal His6 affinity tag and a c-terminal FLAG affinity tag to aidin purification. The recombinant Bacmid was isolated and used totransfect insect cells to generate a viral stock. To generate cell pastefor purification, insect cells were infected with the virus stock andcells were harvested 72 hours after infection. Insect cell paste waslysed and after centrifugation, the supernatant was batch bound toNi-NTA agarose (GE Healthcare) and eluted with 250 mM imidazole. Thiseluate was diluted with FLAG buffer (50 mM Tris HCL pH 7.5, 100 mM NaCl,5% Glycerol, 1 mM TCEP with protease inhibitors) and batch bound toant-FLAG M2 agarose (Sigma) overnight at 4° C. The agarose was packedinto a column, washed with buffer and eluted with buffer containingelute using 250 ug/ml Flag-peptide. Fractions were analyzed usingSDS-PAGE Coomassie blue staining and pooled based on purity. Pooledfractions were chromatographed on a S200 120 ml column (GE Healthcare)in 50 mM Tris HCL pH 7.5, 150 mM NaCl, 10% Glycerol, 2 mM TCEP withprotease inhibitors. PDE4C1 fractions were analyzed by SDS-PAGECoomassie blue staining, pooled based on purity, dialyzed against 50 mMTris HCL pH 7.5, 100 mM NaCl, 20% Glycerol, 2 mM TCEP, frozen and storedat −80° C.

A portion of the human PDE4D3 coding sequence (amino acids 50 to 672from the sequence with accession number Q08499-2) was cloned into thebaculovirus expression vector pFastBac (Invitrogen) engineered toinclude a C-terminal His6 affinity tag to aid in purification asdescribed in Seeger, T. F. et al., Brain Research 985 (2003) 113-126.The recombinant Bacmid was isolated and used to transfect insect cellsto generate a viral stock. To generate cell paste for purification,insect cells were infected and cells were harvested 72 hours afterinfection. Insect cell paste was lysed and after centrifugation, thesupernatant was chromatographed on Ni-NTA agarose (Qiagen) as describedin Seeger, T. F. et al., Brain Research 985 (2003) 113-126. Ni-NTAagarose eluting fractions containing PDE4 were pooled, diluted with QBuffer A (50 mM Tris HCl pH 8, 4% glycerol, 100 mM NaCl, 1 mM TCEP,Protease inhibitors EDTA-free (Roche)) to reduce NaCl to −200 mM, andloaded on a Q Sepharose (GE Healthcare) column. After washing with Qbuffer A to baseline, PDE4D was eluted with a gradient from 10% to 60%of Buffer B (50 mM Tris HCl pH 8, 1 M NaCl, 4% glycerol, 1 mM TCEP).PDE4D fractions were analyzed by SDS-PAGE Coomassie blue staining,pooled based on purity, frozen and stored at −80° C.

The PDE4A3, PDE4B1, PDE4C1 and PDE4D3 assays use the ScintillationProximity Assay (SPA) technology to measure the inhibition of humanrecombinant PDE4A1, PDE4B3, PDE4C1, and PDE4D3 enzyme activity bycompounds in vitro. The PDE4A1, PDE4B3, PDE4C1, and PDE4D3 assays arerun in parallel using identical parameters, except for the concentrationof enzyme (80 pM PDE4A3, 40 pM PDE4B3, 40 pM PDE4C1 and 10 pM PDE4D).The assays are performed in a 384-well format with 50 uL assay buffer(50 mM TRIS pH7.5; 1.3 mM MgCl2; 0.01% Brij) containing enough PDE4A3,PDE4B1, PDE4C1, and PDE4D to convert ˜20% of substrate (1 μM cAMPconsisting of 20 nM 3H-cAMP+980 uM cold cAMP) and a range of inhibitors.Reactions are incubated for 30 min at 25° C. The addition of 20 uL of 8mg/ml yitrium silicate SPA beads (Perkin Elmer) stops the reaction. Theplates are sealed (TopSeal, Perkin Elmer) and the beads are allowed tosettle for 8 hrs, after which they are read on the Trilux Microbetaovernight.

TABLE 3 Biological data for Examples 1-104. Human Human Human HumanExample PDE4A FL; PDE4B FL; PDE4C FL; PDE4D FL; Number IC₅₀ (nM)^(b)IC₅₀ (nM)^(b) IC₅₀ (nM)^(b) IC₅₀ (nM)^(b) IUPAC Name 1 38.6   35.5^(c)130   10300^(c) azetidin-1-yl[3-(4- chlorophenyl)imidazo[1,2-b]pyridazin-2-yl]methanone 2 10.7 17.7 27.9   4340^(c)3-(4-chlorophenyl)-N- cyclopropylimidazo[1,2- b]pyridazine-2-carboxamide3 12.7 29.1 51.9 2410 azetidin-1-yl[3-(3,5- difluoro-4-methoxyphe-nyl)imidazo[1,2-b]pyridazin- 2-yl]methanone 4 187   380^(c  ) 561  >27100^(c ) N-cyclopropyl-3-(2-methoxy- pyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carboxamide 5 40.2 89.5 208   >26600 3-(6-cyanopyridin-3-yl)-N- cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide 6 64.4 49.3 326     4890^(c)N-cyclopropyl-3-([1,2,4]tri- azolo[1,5-a]pyridin-6-yl)imidazo[1,2-b]pyridazine- 2-carboxamide 7  2.77  <1.89  2.35   34.53-(4-chloro-3-fluorophenyl)- N-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine- 2-carboxamide 8 20.0   41.3^(c) 64.9  5440^(c) azetidin-1-yl[3- (pyrazolo[1,5-a]pyridin-6-yl)imidazo[1,2-b]pyridazin- 2-yl]methanone 9  3.83 10.5 40.9 14903-(4-chloro-2,5-difluoro- phenyl)-N-cyclopropyl-imidazo[1,2-b]pyridazine- 2-carboxamide 10  1.51    3.80^(c)  6.84   590^(c) 3-(4-chloro-3-fluoro- phenyl)-N-cyclopropyl-imidazo[1,2-b]pyridazine- 2-carboxamide 11 ND  1.60 ND    334^(c)N-cyclopropyl-3-(3,4-di- chlorophenyl)imidazo[1,2-b]pyridazine-2-carboxamide 12 14.4   35.8^(c) 89.6   5220^(c)3-(4-chloro-2-methyl- phenyl)-N-cyclopropyl- imidazo[1,2-b]pyridazine-2-carboxamide 13  5.13    4.63^(c) 17.3    669^(c)azetidin-1-yl[3-(4-chloro- 3-fluorophenyl)imidazo[1,2-b]pyridazin-2-yl]methanone 14 73.7   79.1^(c) 108   >8010^(c )3-(5-chloropyridin-3-yl)- N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide 15 264   252^(c  ) 421   >23700^(c )azetidin-1-yl[3-(5-chloro- pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl]methanone 16 ND 552   ND >27500 azetidin-1-yl[3-([1,2,4]tri- azolo[1,5-a]pyridin-6-yl)imidazo[1,2-b]pyridazin- 2-yl]methanone 17 89.9 175^(c  ) 216  >18200^(c ) 3-(4-cyano-2-fluoro-5- methylphenyl)-N-cyclopropyl-imidazo[1,2-b]pyridazine- 2-carboxamide 18 55.0 150   147   82004-[2-(azetidin-1- ylcarbonyl)imidazo[1,2- b]pyridazin-3-yl]-5-fluoro-2-methylbenzonitrile 19 16.9 13.6 98.4  6453-(4-cyano-5-fluoro-2- methylphenyl)-N-cyclo- propylimidazo[1,2-b]pyridazine-2-carboxamide 20  6.70    5.74^(c) 74.8    490^(c)4-[2-(azetidin-1- ylcarbonyl)imidazo[1,2- b]pyridazin-3-yl]-2-fluoro-5-methylbenzonitrile 21 53.7   91.3^(c) 170   >12300^(c )3-(4-chloro-3-fluorophenyl)- N-cyclopropyl-N-methyl-imidazo[1,2-b]pyridazine- 2-carboxamide 22 27.6 58.9 71.2 1890N-cyclopropyl-3- (pyrazolo[1,5-a]pyridin-6- yl)imidazo[1,2-b]pyridazine-2-carboxamide 23 15.1 30.5 45.8 4130 4-[2-(azetidin-1-ylcarbonyl)imidazo[1,2- b]pyridazin-3-yl]-2- fluorobenzonitrile 24  5.0419.1 59.7 >2150  4-[2-(azetidin-1- ylcarbonyl)imidazo[1,2-b]pyridazin-3-yl]-2,5- difluorobenzonitrile 25 38.6 140   150   49703-(4-chloro-5-fluoro-2- methylphenyl)-N-methyl-imidazo[1,2-b]pyridazine- 2-carboxamide 26 85.5 114   111     3800^(c)3-(4-chlorophenyl)-N-propyl- imidazo[1,2-b]pyridazine-2- carboxamide 27742   609   768     5620^(c) [3-(4-chlorophenyl)imidazo[1,2-b]pyridazin-2-yl](pyrrolidin- 1-yl)methanone 28 15.6 31.7 49.0   393^(c) 3-(3,5-dichlorophenyl)- N-propylimidazo[1,2-b]pyridazine-2-carboxamide 29  3.48  5.05 13.8   409^(c)3-(4-chloro-3-fluorophenyl)- N-propylimidazo[1,2-b]pyridazine-2-carboxamide 30 11.6 55.0 24.5   4000^(c)3-(4-chlorophenyl)-N-(2- methylcyclopropyl)imidazo[1,2-b]pyridazine-2-carboxamide 31 2820   2670   5810   >26200 [3-(4-chlorophenyl)imidazo[1,2- b]pyridazin-2-yl](3-methoxy-azetidin-1-yl)methanone 32 1030   419^(c  ) 469   >30000^(c )3-(4-chlorophenyl)-N-cyclo- propyl-N-methyl-imidazo[1,2-b]pyridazine-2-carboxamide 33 58.6 53.6 127   23303-(4-chlorophenyl)-N-(1- methylcyclopropyl)imidazo[1,2-b]pyridazine-2-carboxamide 34 29.5   83.2^(c) 47.0   2110^(c)3-(3-chloro-5-fluorophenyl)- N-propylimidazo[1,2-b]pyridazine-2-carboxamide 35 35.7 48.0 37.0 12203-(3-chloro-5-fluorophenyl)- N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide 36 23.7  6.99 21.0  254 3-(3-chlorophenyl)-N-cyclopropylimidazo[1,2- b]pyridazine-2-carboxamide 37 127   75.3 161  2570 N-(bicyclo[1.1.1]pent-1-yl)- 3-(4-chlorophenyl)imidazo[1,2-b]pyridazine-2-carboxamide 38 ND 268   ND 11200 N-cyclopropyl-3-(furo[3,2- b]pyridin-6-yl)imidazo[1,2-b]pyridazine-2-carboxamide 39 14.8 26.5 67.8   3820^(b)3-(1,3-benzoxazol-5-yl)-N- cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide 40 19.6 65.3 58.1 90203-(4-chloro-2-fluorophenyl)- N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide 41  3.13  8.05 16.8  467N-cyclopropyl-3-(3-fluoro- 4-methylphenyl)imidazo[1,2-b]pyridazine-2-carboxamide 42 415   393^(c  ) 357   >12200^(c )N-cyclopropyl-3-[2-(tri- fluoromethyl)pyridin-4-yl]imidazo[1,2-b]pyridazine- 2-carboxamide 43 ND 270   ND >16900 azetidin-1-yl{3-[2-(tri- fluoromethyl)pyridin-4-yl]imidazo[1,2-b]pyridazin- 2-yl}methanone 44 ND  3.92 ND  3203-(4-chloro-3-fluorophenyl)- N-(2,2-difluorocyclopro-pyl)imidazo[1,2-b]pyridazine- 2-carboxamide 45  2.91  1.97 11.7  1593-(4-chloro-3-fluorophenyl)- N-[(1R,2S)-2-fluorocyclopro-pyl]imidazo[1,2-b]pyridazine- 2-carboxamide 46 15.2 12.3 39.3  9713-(4-chlorophenyl)-N- [(1R,2S)-2-fluorocyclopro-pyl]imidazo[1,2-b]pyridazine- 2-carboxamide 47  7.37    3.90^(c) 23.9   334^(c) azetidin-1-yl[3-(4-chloro-3,5- difluorophenyl)imidazo[1,2-b]pyridazin-2-yl]methanone 48 768   322   212   >7670 3-(5-chloropyridin-3-yl)- N-propylimidazo[1,2-b]pyridazine-2-carboxamide 49  4.16 13.3 19.0    535^(b)azetidin-1-yl[3-(3-chloro- 4-methylphenyl)imidazo[1,2-b]pyridazin-2-yl]methanone 50 28.1 116   235   3140azetidin-1-yl[3-(2,3-dihydro- 1-benzofuran-5-yl)imidazo[1,2-b]pyridazin-2-yl]methanone 51 ND 42.9 ND 2810 azetidin-1-yl[3-(4-chloro-3-methylphenyl)imidazo[1,2- b]pyridazin-2-yl]methanone 52 24.3 37.3113   5510 azetidin-1-yl[3-(4-chloro- 2-fluorophenyl)imidazo[1,2-b]pyridazin-2-yl]methanone 53 17.8 63.3 153   3110azetidin-1-yl[3-(4-fluoro-3,5- dimethylphenyl)imidazo[1,2-b]pyridazin-2-yl]methanone 54 103   107^(c  ) 136   >20000^(c )azetidin-1-yl[3-(2-fluoro- 4-methylphenyl)imidazo[1,2-b]pyridazin-2-yl]methanone 55 176   200   >1550    >20900^(c )azetidin-1-yl[3-(3-fluoro- 4-methoxyphenyl)imidazo[1,2-b]pyridazin-2-yl]methanone 56 22.7   43.1^(c) 84.5   3930^(c)azetidin-1-yl[3-(4-chloro- 2-methylphenyl)imidazo[1,2-b]pyridazin-2-yl]methanone 57 ND 236   ND >21800 3-(4-chlorophenyl)-N-[2-(2- hydroxyphenyl)ethyl]imidazo[1,2-b]pyridazine-2-carboxamide, formate salt 58 ND 43.3 ND  8313-(4-chlorophenyl)-N-(5-methyl- 1,2-oxazol-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide, trifluoroacetate salt 59 ND 58.5 ND  7493-(4-chlorophenyl)-N-(2-methyl- 2H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide, trifluoroacetate salt 60 269   196  287   >4930  [3-(4-chlorophenyl)imidazo[1,2-b]pyridazin-2-yl](3-fluoroazetidin- 1-yl)methanone 61 144   184   126  1930 [3-(4-chlorophenyl)imidazo[1,2- b]pyridazin-2-yl](3,3-di-fluoroazetidin-1-yl)methanone 62 ND 275   ND 11000 azetidin-1-yl[3-(quinoxalin-6- yl)imidazo[1,2-b]pyridazin-2-yl]methanone, formate salt 63 ND 17.7 ND  394 1-{3-[2-(azetidin-1-ylcarbonyl)imidazo[1,2- b]pyridazin-3-yl]-4-fluoro- phenyl}ethanone,formate salt 64 ND 24.2 ND  844 azetidin-1-yl[3-(5-chloro-2-methylphenyl)imidazo[1,2- b]pyridazin-2-yl]methanone 65 ND 71.9 ND 3720azetidin-1-yl[3-(2,4- dichlorophenyl)imidazo[1,2-b]pyridazin-2-yl]methanone 66 ND 41.0 ND 3390azetidin-1-yl[3-(3-chloro-2,4- dimethylphenyl)imidazo[1,2-b]pyridazin-2-yl]methanone, formate salt 67 ND 59.8 ND 2260azetidin-1-yl[3-(2,3-dihydro- 1,4-benzodioxin-6-yl)imidazo[1,2-b]pyridazin-2-yl]methanone, formate salt 68 10.6 35.4 25.1 26203-(4-chloro-2-fluorophenyl)-N- [(1R,2S)-2-fluorocyclopro-pyl]imidazo[1,2-b]pyridazine- 2-carboxamide 69 ND 116   ND 33303-(5-chloropyridin-3-yl)-N- [(1R,2S)-2-fluorocyclopro-pyl]imidazo[1,2-b]pyridazine- 2-carboxamide 70 36.4   31.0^(c) 90.0  5760^(c) 3-(4-chloro-2-methylphenyl)-N- [(1R,2S)-2-fluorocyclopro-pyl]imidazo[1,2-b]pyridazine- 2-carboxamide 71  <0.669  2.82  2.00  1133-(3-chloro-4-methylphenyl)-N- [(1R,2S)-2-fluorocyclopro-pyl]imidazo[1,2-b]pyridazine- 2-carboxamide 72 ND 192   ND 6590N-[(1R,2S)-2-fluorocyclopro- pyl]-3-(2-fluoro-4-methyl-phenyl)imidazo[1,2- b]pyridazine-2-carboxamide 73 165   495  1440   >24700  azetidin-1-yl[3-(2-fluoro-4- methoxyphenyl)imidazo[1,2-b]pyridazin-2-yl]methanone 74 ND 225   ND 10500 azetidin-1-yl[3-(pyrazolo[1,5- a]pyrimidin-6-yl)imidazo[1,2-b]pyridazin-2-yl]methanone 75 10.5    5.99^(c) 24.9    104^(c)N-cyclopropyl-3-[2-(difluoro- methoxy)pyridin-4-yl]imidazo[1,2-b]pyridazine-2-carboxamide 76  7.09    5.43^(c) 22.2    94.5^(c)azetidin-1-yl{3-[2-(difluoro- methoxy)pyridin-4-yl]imidazo[1,2-b]pyridazin-2-yl}methanone 77 46.1   80.4^(c) 186   >16600^(c )azetidin-1-yl[3-(1,3-ben- zoxazol-6-yl)imidazo[1,2-b]pyridazin-2-yl]methanone 78 ND 364   ND 6490N-cyclopropyl-3-(pyrazolo[1,5- a]pyrimidin-6-yl)imidazo[1,2-b]pyridazine-2-carboxamide 79 48.8 190^(c  ) 297   >25400^(c )3-(4-cyano-2-fluorophenyl)-N- cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide 80 ND 344   ND >25400 3-(5-cyano-2-methylphenyl)-N- cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide 81  7.86    9.34^(c) 25.8    853^(c)3-(4-chloro-3-fluorophenyl)- N-ethylimidazo[1,2-b]pyridazine-2-carboxamide 82 12.0  5.14 43.4   56.53-(4-chloro-3-fluorophenyl)- N-(1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide 83  6.21  5.39 40.0  495azetidin-1-yl[3-(3,4-dichloro- phenyl)imidazo[1,2-b]pyridazin-2-yl]methanone 84 16.7    7.84^(c) 44.4    977^(c)azetidin-1-yl[3-(3-chloro- phenyl)imidazo[1,2-b]pyridazin-2-yl]methanone 85 25.6   87.3^(c) 47.2   6700^(c)3-(4-chlorophenyl)-N- ethylimidazo[1,2- b]pyridazine-2-carboxamide 86 5.83  7.72 25.0  179 azetidin-1-yl[3-(2,2- difluoro-1,3-benzodioxol-5-yl)imidazo[1,2- b]pyridazin-2-yl]methanone 87 240   173   397   6790N-cyclopropyl-3-[6- (difluoromethoxy)pyridin- 3-yl]imidazo[1,2-b]pyridazine-2-carboxamide 88 45.0   39.2^(c) 136   10400^(c)3-(1,3-benzoxazol-6-yl)- N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide 89 829   333   3760   >17200 N-cyclopropyl-3-(7- methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazo[1,2- b]pyridazine-2-carboxamide 90 21.4 43.7 25.52620 3-(4-cyano-3-fluorophenyl)- N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide 91 12.6 36.9 80.0 2250azetidin-1-yl[3-(4-chloro- 2,5-difluorophenyl)imidazo[1,2-b]pyridazin-2-yl]methanone 92  5.52 21.0 42.5 >1440 3-(4-cyano-2,5-difluorophenyl)- N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide 93 62.9 276   134   41103-(4-chloro-2,5-difluorophenyl)- N-methylimidazo[1,2-b]pyridazine-2-carboxamide 94 24.9 253   65.0 53803-(4-chloro-3-fluorophenyl)- N-methylimidazo[1,2-b]pyridazine-2-carboxamide 95 ND 306   ND 14800 3-(4-chloro-2-methylphenyl)- N-ethylimidazo[1,2-b]pyridazine-2-carboxamide 96  4.58 33.2 29.2  9083-(4-chloro-2,5-difluoro- phenyl)-N-ethylimidazo[1,2-b]pyridazine-2-carboxamide 97  5.48 23.3 20.0 >1850 3-(4-chloro-5-fluoro-2- methylphenyl)-N-(propan-2-yl)imidazo[1,2-b]pyridazine- 2-carboxamide 98 26.6 62.7 107   33203-(4-cyano-5-fluoro-2-methyl- phenyl)-N-ethylimidazo[1,2-b]pyridazine-2-carboxamide 99 19.8 36.2 138   15503-(4-cyano-5-fluoro-2- methylphenyl)-N-(propan-2-yl)imidazo[1,2-b]pyridazine- 2-carboxamide 100 ND 49.1 ND  7663-(4-chloro-2,5-difluoro- phenyl)-N-(propan-2-yl)imidazo[1,2-b]pyridazine- 2-carboxamide 101 268^(a)    861  1179^(a)    >25900  3-(4-chlorophenyl)-N- (pyrimidin-2-yl)imidazo[1,2-b]pyridazine-2-carboxamide 102 59.9 103   76.0 50103-(4-chlorophenyl)-N-(cyclo- propylmethyl)imidazo[1,2-b]pyridazine-2-carboxamide 103 62.7 249   203   15503-(4-chlorophenyl)-N-(1H- pyrazol-5-yl)imidazo[1,2-b]pyridazine-2-carboxamide 104  <0.488  1.59  4.69  1453-(4-chloro-3,5-difluoro- phenyl)-N-cyclopropyl-imidazo[1,2-b]pyridazine- 2-carboxamide ^(a)Values represents 1determination ^(b)Values represent the geometric mean of 2-9determinations, unless otherwise indicated. ^(c)Value represents thegeometric mean of ≥10 determinations ND. Value not determined

What is claimed:
 1. A compound selected from the group consisting of:3-(4-chlorophenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide;azetidin-1-yl[3-(3,5-difluoro-4-methoxyphenyl)imidazo[1,2-b]pyridazin-2-yl]methanone;N-cyclopropyl-3-(2-methoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carboxamide;3-(4-chloro-3-fluorophenyl)-N-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide;azetidin-1-yl[3-(pyrazolo[1,5-a]pyridin-6-yl)imidazo[1,2-b]pyridazin-2-yl]methanone;3-(4-chloro-3-fluorophenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide;N-cyclopropyl-3-(3,4-dichlorophenyl)imidazo[1,2-b]pyridazine-2-carboxamide;3-(4-chloro-2-methylphenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide;azetidin-1-yl[3-(4-chloro-3-fluorophenyl)imidazo[1,2-b]pyridazin-2-yl]methanone;3-(5-chloropyridin-3-yl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide;azetidin-1-yl[3-(5-chloropyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl]methanone;azetidin-1-yl[3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazo[1,2-b]pyridazin-2-yl]methanone;3-(4-cyano-2-fluoro-5-methylphenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide;4-[2-(azetidin-1-ylcarbonyl)imidazo[1,2-b]pyridazin-3-yl]-5-fluoro-2-methylbenzonitrile;3-(4-cyano-5-fluoro-2-methylphenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide;3-(4-chloro-3-fluorophenyl)-N-cyclopropyl-N-methylimidazo[1,2-b]pyridazine-2-carboxamide;N-cyclopropyl-3-(pyrazolo[1,5-a]pyridin-6-yl)imidazo[1,2-b]pyridazine-2-carboxamide;4-[2-(azetidin-1-ylcarbonyl)imidazo[1,2-b]pyridazin-3-yl]-2-fluorobenzonitrile;4-[2-(azetidin-1-ylcarbonyl)imidazo[1,2-b]pyridazin-3-yl]-2,5-difluorobenzonitrile;3-(4-chloro-5-fluoro-2-methylphenyl)-N-methylimidazo[1,2-b]pyridazine-2-carboxamide;3-(4-chlorophenyl)-N-propylimidazo[1,2-b]pyridazine-2-carboxamide;[3-(4-chlorophenyl)imidazo[1,2-b]pyridazin-2-yl](pyrrolidin-1-yl)methanone;3-(3,5-dichlorophenyl)-N-propylimidazo[1,2-b]pyridazine-2-carboxamide;3-(4-chloro-3-fluorophenyl)-N-propylimidazo[1,2-b]pyridazine-2-carboxamide;3-(4-chlorophenyl)-N-(2-methylcyclopropyl)imidazo[1,2-b]pyridazine-2-carboxamide;[3-(4-chlorophenyl)imidazo[1,2-b]pyridazin-2-yl](3-methoxyazetidin-1-yl)methanone;3-(4-chlorophenyl)-N-cyclopropyl-N-methylimidazo[1,2-b]pyridazine-2-carboxamide;3-(4-chlorophenyl)-N-(1-methylcyclopropyl)imidazo[1,2-b]pyridazine-2-carboxamide;3-(3-chloro-5-fluorophenyl)-N-propylimidazo[1,2-b]pyridazine-2-carboxamide;3-(3-chloro-5-fluorophenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide;3-(3-chlorophenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide;N-(bicyclo[1.1.1]pent-1-yl)-3-(4-chlorophenyl)imidazo[1,2-b]pyridazine-2-carboxamide;N-cyclopropyl-3-(furo[3,2-b]pyridin-6-yl)imidazo[1,2-b]pyridazine-2-carboxamide;3-(1,3-benzoxazol-5-yl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide;3-(4-chloro-2-fluorophenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide;N-cyclopropyl-3-(3-fluoro-4-methylphenyl)imidazo[1,2-b]pyridazine-2-carboxamide;N-cyclopropyl-3-[2-(trifluoromethyl)pyridin-4-yl]imidazo[1,2-b]pyridazine-2-carboxamide;azetidin-1-yl{3-[2-(trifluoromethyl)pyridin-4-yl]imidazo[1,2-b]pyridazin-2-yl}methanone;3-(4-chloro-3-fluorophenyl)-N-(2,2-difluorocyclopropyl)imidazo[1,2-b]pyridazine-2-carboxamide;3-(4-chloro-3-fluorophenyl)-N-[(1R,2S)-2-fluorocyclopropyl]imidazo[1,2-b]pyridazine-2-carboxamide;3-(4-chlorophenyl)-N-[(1R,2S)-2-fluorocyclopropyl]imidazo[1,2-b]pyridazine-2-carboxamide;azetidin-1-yl[3-(4-chloro-3,5-difluorophenyl)imidazo[1,2-b]pyridazin-2-yl]methanone;3-(5-chloropyridin-3-yl)-N-propylimidazo[1,2-b]pyridazine-2-carboxamide;azetidin-1-yl[3-(3-chloro-4-methylphenyl)imidazo[1,2-b]pyridazin-2-yl]methanone;azetidin-1-yl[3-(2,3-dihydro-1-benzofuran-5-yl)imidazo[1,2-b]pyridazin-2-yl]methanone;azetidin-1-yl[3-(4-chloro-3-methylphenyl)imidazo[1,2-b]pyridazin-2-yl]methanone;azetidin-1-yl[3-(4-chloro-2-fluorophenyl)imidazo[1,2-b]pyridazin-2-yl]methanone;azetidin-1-yl[3-(4-fluoro-3,5-dimethylphenyl)imidazo[1,2-b]pyridazin-2-yl]methanone;azetidin-1-yl[3-(2-fluoro-4-methylphenyl)imidazo[1,2-b]pyridazin-2-yl]methanone;azetidin-1-yl[3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-b]pyridazin-2-yl]methanone;[3-(4-chlorophenyl)imidazo[1,2-b]pyridazin-2-yl](3-fluoroazetidin-1-yl)methanone;[3-(4-chlorophenyl)imidazo[1,2-b]pyridazin-2-yl](3,3-difluoroazetidin-1-yl)methanone;azetidin-1-yl[3-(5-chloro-2-methylphenyl)imidazo[1,2-b]pyridazin-2-yl]methanone;azetidin-1-yl[3-(2,4-dichlorophenyl)imidazo[1,2-b]pyridazin-2-yl]methanone;3-(4-chloro-2-fluorophenyl)-N-[(1R,2S)-2-fluorocyclopropyl]imidazo[1,2-b]pyridazine-2-carboxamide;3-(5-chloropyridin-3-yl)-N-[(1R,2S)-2-fluorocyclopropyl]imidazo[1,2-b]pyridazine-2-carboxamide;3-(4-chloro-2-methylphenyl)-N-[(1R,2S)-2-fluorocyclopropyl]imidazo[1,2-b]pyridazine-2-carboxamide;3-(3-chloro-4-methylphenyl)-N-[(1R,2S)-2-fluorocyclopropyl]imidazo[1,2-b]pyridazine-2-carboxamide;N-[(1R,2S)-2-fluorocyclopropyl]-3-(2-fluoro-4-methylphenyl)imidazo[1,2-b]pyridazine-2-carboxamide;azetidin-1-yl[3-(2-fluoro-4-methoxyphenyl)imidazo[1,2-b]pyridazin-2-yl]methanone;azetidin-1-yl[3-(pyrazolo[1,5-a]pyrimidin-6-yl)imidazo[1,2-b]pyridazin-2-yl]methanone;N-cyclopropyl-3-[2-(difluoromethoxy)pyridin-4-yl]imidazo[1,2-b]pyridazine-2-carboxamide;azetidin-1-yl[3-(4-chloro-2-methylphenyl)imidazo[1,2-b]pyridazin-2-yl]methanone;azetidin-1-yl{3-[2-(difluoromethoxy)pyridin-4-yl]imidazo[1,2-b]pyridazin-2-yl}methanone;azetidin-1-yl[3-(1,3-benzoxazol-6-yl)imidazo[1,2-b]pyridazin-2-yl]methanone;N-cyclopropyl-3-(pyrazolo[1,5-a]pyrimidin-6-yl)imidazo[1,2-b]pyridazine-2-carboxamide;3-(4-cyano-2-fluorophenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide;3-(5-cyano-2-methylphenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide;3-(4-chloro-3-fluorophenyl)-N-ethylimidazo[1,2-b]pyridazine-2-carboxamide;3-(4-chloro-3-fluorophenyl)-N-(1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide;azetidin-1-yl[3-(3,4-dichlorophenyl)imidazo[1,2-b]pyridazin-2-yl]methanone;azetidin-1-yl[3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-2-yl]methanone;3-(4-chlorophenyl)-N-ethylimidazo[1,2-b]pyridazine-2-carboxamide;azetidin-1-yl[3-(2,2-difluoro-1,3-benzodioxol-5-yl)imidazo[1,2-b]pyridazin-2-yl]methanone;N-cyclopropyl-3-[6-(difluoromethoxy)pyridin-3-yl]imidazo[1,2-b]pyridazine-2-carboxamide;3-(1,3-benzoxazol-6-yl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide;N-cyclopropyl-3-(7-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazo[1,2-b]pyridazine-2-carboxamide;3-(4-cyano-3-fluorophenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide;azetidin-1-yl[3-(4-chloro-2,5-difluorophenyl)imidazo[1,2-b]pyridazin-2-yl]methanone;3-(4-cyano-2,5-difluorophenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide;3-(4-chloro-2,5-difluorophenyl)-N-methylimidazo[1,2-b]pyridazine-2-carboxamide;3-(4-chloro-3-fluorophenyl)-N-methylimidazo[1,2-b]pyridazine-2-carboxamide;3-(4-chloro-2-methylphenyl)-N-ethylimidazo[1,2-b]pyridazine-2-carboxamide;3-(4-chloro-2,5-difluorophenyl)-N-ethylimidazo[1,2-b]pyridazine-2-carboxamide;3-(4-chloro-5-fluoro-2-methylphenyl)-N-(propan-2-yl)imidazo[1,2-b]pyridazine-2-carboxamide;3-(4-cyano-5-fluoro-2-methylphenyl)-N-ethylimidazo[1,2-b]pyridazine-2-carboxamide;3-(4-cyano-5-fluoro-2-methylphenyl)-N-(propan-2-yl)imidazo[1,2-b]pyridazine-2-carboxamide;3-(4-chloro-2,5-difluorophenyl)-N-(propan-2-yl)imidazo[1,2-b]pyridazine-2-carboxamide;3-(4-chlorophenyl)-N-(pyrimidin-2-yl)imidazo[1,2-b]pyridazine-2-carboxamide;3-(4-chlorophenyl)-N-(cyclopropylmethyl)imidazo[1,2-b]pyridazine-2-carboxamide;3-(4-chlorophenyl)-N-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazine-2-carboxamide;and3-(4-chloro-3,5-difluorophenyl)-N-cyclopropylimidazo[1,2-b]pyridazine-2-carboxamide;or a pharmaceutically acceptable salt thereof.
 2. A compound selectedfrom the group consisting of:azetidin-1-yl[3-(3-chloro-2,4-dimethylphenyl)imidazo[1,2-b]pyridazin-2-yl]methanone,formate salt;azetidin-1-yl[3-(2,3-dihydro-1,4-benzodioxin-6-yl)imidazo[1,2-b]pyridazin-2-yl]methanone,formate salt;azetidin-1-yl[3-(quinoxalin-6-yl)imidazo[1,2-b]pyridazin-2-yl]methanone,formate salt;1-{3-[2-(azetidin-1-ylcarbonyl)imidazo[1,2-b]pyridazin-3-yl]-4-fluorophenyl}ethanone,formate salt;3-(4-chlorophenyl)-N-[2-(2-hydroxyphenyl)ethyl]imidazo[1,2-b]pyridazine-2-carboxamide,formate salt;3-(4-chlorophenyl)-N-(5-methyl-1,2-oxazol-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide,trifluoroacetate salt; and3-(4-chlorophenyl)-N-(2-methyl-2H-1,2,3-triazol-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide,trifluoroacetate salt. 3.3-(4-chloro-2-methylphenyl)-N-[(1R,2S)-2-fluorocyclopropyl]imidazo[1,2-b]pyridazine-2-carboxamide,or a pharmaceutically acceptable salt thereof. 4.3-(4-chloro-5-fluoro-2-methylphenyl)-N-(propan-2-yl)imidazo[1,2-b]pyridazine-2-carboxamide,or a pharmaceutically acceptable salt thereof.
 5. A pharmaceuticalcomposition comprising the compound according to claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 6. A pharmaceutical composition comprising thecompound according to claim 3, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable excipient.
 7. Apharmaceutical composition comprising the compound according to claim 4,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.